U.S. patent application number 14/372986 was filed with the patent office on 2014-11-27 for novel 2-amino-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo [4,5-d]azepine derivatives and their use as allosteric modulators of metabotropic glutamate receptors.
The applicant listed for this patent is Addex Pharma S.A.. Invention is credited to Christelle Bolea, Cedric Boudou, Sylvain Celanire, Vincent Darmency, Celine Mordant, Vincent Pericolle, Yannick Regereau, Jean-Philippe Rocher, Radouane Souissi, Lam Tang.
Application Number | 20140349994 14/372986 |
Document ID | / |
Family ID | 47605510 |
Filed Date | 2014-11-27 |
United States Patent
Application |
20140349994 |
Kind Code |
A1 |
Bolea; Christelle ; et
al. |
November 27, 2014 |
Novel 2-Amino-4,5,6,8-Tetrahydropyrazolo[3,4-b]Thiazolo
[4,5-d]Azepine Derivatives and Their Use as Allosteric Modulators
of Metabotropic Glutamate Receptors
Abstract
The present invention relates to novel compounds of Formula (I),
wherein M and R.sup.1 are defined as in Formula (I); invention
compounds are modulators of metabotropic glutamate
receptors--subtype 4 ("mGluR.sub.4") which are useful for the
treatment or prevention of central nervous system disorders as well
as other disorders modulated by mGluR.sub.4 receptors. The
invention is also directed to pharmaceutical compositions and the
use of such compounds in the manufacture of medicaments, as well as
to the use of such compounds for the prevention and treatment of
such diseases in which mGluR.sub.4 is involved. ##STR00001##
Inventors: |
Bolea; Christelle; (Geneva,
CH) ; Boudou; Cedric; (Geneva, CH) ; Celanire;
Sylvain; (Geneva, CH) ; Darmency; Vincent;
(Geneva, CH) ; Mordant; Celine; (Geneva, CH)
; Pericolle; Vincent; (Geneva, CH) ; Regereau;
Yannick; (Geneva, CH) ; Rocher; Jean-Philippe;
(Geneva, CH) ; Souissi; Radouane; (Geneva, CH)
; Tang; Lam; (Geneva, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Addex Pharma S.A. |
Geneva |
|
CH |
|
|
Family ID: |
47605510 |
Appl. No.: |
14/372986 |
Filed: |
January 18, 2013 |
PCT Filed: |
January 18, 2013 |
PCT NO: |
PCT/EP2013/050945 |
371 Date: |
July 17, 2014 |
Current U.S.
Class: |
514/210.21 ;
426/537; 514/215; 540/578 |
Current CPC
Class: |
C07D 513/04 20130101;
C07D 513/14 20130101; A23L 27/2056 20160801; A61K 31/55 20130101;
A61K 45/06 20130101; A61P 25/28 20180101; A23L 2/56 20130101; A23L
33/10 20160801 |
Class at
Publication: |
514/210.21 ;
540/578; 514/215; 426/537 |
International
Class: |
C07D 513/14 20060101
C07D513/14; A23L 1/30 20060101 A23L001/30; A23L 1/226 20060101
A23L001/226; A23L 2/56 20060101 A23L002/56; A61K 31/55 20060101
A61K031/55; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 2012 |
GB |
1200800.9 |
Sep 18, 2012 |
GB |
1216657.5 |
Claims
1. A compound having the Formula (I) wherein: ##STR00336## a
pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof and an N-oxide form thereof,
wherein: M is an optionally substituted heteroaryl; R.sup.1 is
hydrogen or an optionally substituted radical selected from the
group of --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.1-C.sub.6)alkylene-aryl, aryl,
--(C.sub.1-C.sub.6)alkylene-hetero aryl, heteroaryl,
--(C.sub.1-C.sub.6)alkylene-hetero cycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-OR.sup.2,
--(C.sub.2-C.sub.6)alkylene-NR.sup.2R.sup.3,
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--NR.sup.2R.sup.3,
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.2; R.sup.2 and R.sup.3
are each independently hydrogen or an optionally substituted
radical selected from the group of --(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)cyanoalkyl,
--(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-hetero aryl,
aryl, --(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N-((C.sub.0-C.sub.6)alkyl).sub.2;
R.sup.2 and R.sup.3 may be taken together to form an optionally
substituted 3 to 10 membered carbocyclic or heterocyclic ring; and
provided that the compound is not:
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Methoxyethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-Methoxypropan-2-yl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Methoxyethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine
N-(6-Fluoropyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N,N-Dimethyl-2-(2-(4-methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-6(8H)-yl)acetamide
6-(2-Methoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Methoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,8-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
2-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)ethanol
N.sup.2-(6-(2-Methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-yl) pyridine-2,6-diamine
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydrofuran-3-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-(methylamino)ethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxypropyl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(6-fluoropyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-isopropoxyethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]aze-
pin-2-ylamino)pyrimidin-5-ol
N-(5-Fluoropyrimidin-2-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(6-(6-(2-Methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]az-
epin-2-ylamino)pyridin-2-yl)methanol
6-(2-Methoxyethyl)-N-(2-methylpyrimidin-4-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Methoxyethyl)-N-(pyrimidin-4-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]th-
iazolo[4,5-d]azepin-2-amine
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-phenethyl-4,5,6,7-tetrahydropyrazolo[3,4-b]t-
hiazolo[4,5-d]azepin-2-amine
N-(3-Fluoro-6-methylpyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-(pyridin-2-yl)ethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-(5-Chloropyridin-2-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Cyclobutyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]-
thiazolo[4,5-d]azepin-2-amine and
N-(6-(Fluoromethyl)pyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
2. A compound according to claim 1 having the Formula (II):
##STR00337## a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof and an
N-oxide form thereof, wherein: (A).sub.m are each independently
selected from the group of hydrogen, halogen, --CN, --OH,
--CF.sub.3, --OCF.sub.3, --NH.sub.2 and an optionally substituted
radical selected from the group of --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.4,
--(C.sub.0-C.sub.6)alkylene-NR.sup.4R.sup.5 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.4; m is an integer
ranging from 1 to 2; R.sup.4 and R.sup.5 are each independently
hydrogen or an optionally substituted radical selected from the
group of --(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N-((C.sub.0-C.sub.6)alkyl).sub.2; and
provided that the compound is not:
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Methoxyethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-Methoxypropan-2-yl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N,N-Dimethyl-2-(2-(4-methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-6(8H)-yl)acetamide
6-(2-Methoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
2-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)ethanol
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydrofuran-3-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-(methylamino)ethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxypropyl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-isopropoxyethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]aze-
pin-2-ylamino)pyrimidin-5-ol
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo [3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-phenethyl-4,5,6,7-tetrahydropyrazolo[3,4-b]t-
hiazolo[4,5-d]azepin-2-amine
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo [3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-(pyridin-2-yl)ethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-(5-Chloropyridin-2-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and
6-Cyclobutyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]-
thiazolo[4,5-d]azepin-2-amine.
3. A compound according to claim 1 having the Formula (III)
wherein: ##STR00338## a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof and
an N-oxide form thereof, wherein: Q is an optionally substituted
aryl, heteroaryl, heterocycle or cycloalkyl; (B) are each
independently selected from the group of hydrogen, halogen, --CN,
--OH, --CF.sub.3, --OCF.sub.3, --NH.sub.2 and an optionally
substituted radical selected from the group of
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.6,
--(C.sub.0-C.sub.6)alkylene-NR.sup.6R.sup.7 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.6; n is an integer
ranging from 1 to 2; R.sup.6 and R.sup.7 are each independently
hydrogen or an optionally substituted radical selected from the
group of --(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-hetero aryl,
aryl, --(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N-((C.sub.0-C.sub.6)alkyl).sub.2; and
provided that the compound is not:
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(6-fluoropyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
4. A compound according to claim 3 having the Formula (IV) wherein:
##STR00339## a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof and an
N-oxide form thereof, wherein: (A).sub.m are each independently
selected from the group of hydrogen, halogen, --CN, --OH,
--CF.sub.3, --OCF.sub.3, --NH.sub.2 and an optionally substituted
radical selected from the group of --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.4,
--(C.sub.0-C.sub.6)alkylene-NR.sup.4R.sup.5 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.4; m is an integer
ranging from 1 to 2; R.sup.4 and R.sup.5 are each independently
hydrogen or an optionally substituted radical selected from the
group of --(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N-((C.sub.0-C.sub.6)alkyl).sub.2; and
provided that the compound is not:
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
5. A compound according to claim 3 having the Formula (III)
wherein: M is selected from the group of formula: ##STR00340## is
selected from the group of formula: ##STR00341##
6. A compound according to claim 5 having the Formula (III)
wherein: M is: ##STR00342## is selected from the group of formula:
##STR00343##
7. A compound according to claim 1 having the Formula (I) wherein:
M is selected from the group of formula: ##STR00344## and R.sup.1
is selected from the group of formula: ##STR00345##
8. A compound according to claim 7 having the Formula (I) wherein:
M is: ##STR00346## and R.sup.1 is selected from the group of
formula: ##STR00347##
9. A compound according to claim 1 having the Formula (I) wherein:
M is selected from the group of formula: M is: ##STR00348## and
R.sup.1 is selected from the group of formula: ##STR00349##
10. A compound according to claim 3 having the Formula (IV)
wherein: M is: ##STR00350## is selected from the group of formula:
##STR00351##
11. A compound according to claims 1 to 10, which can exist as
optical isomers, wherein said compound is either the racemic
mixture or one or both of the individual optical isomers.
12. A compound according to claims 1 to 11, wherein said compound
is selected from:
3-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile
6-(3-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclopropylmethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Cyclopropylisoxazol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and a
pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof and an N-oxide form
thereof.
13. A compound according to claims 1 to 11, wherein said compound
is selected from:
6-((2,3-Dihydrobenzofuran-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Cyclopropylisoxazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropylthiazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-Methoxypropan-2-yl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Chloropyridin-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxycyclobutyl)-4,5,6,7-tetrahydropyra-
zolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-
-b]thiazolo[4,5-d]azepin-2-amine
6-(3,3-Difluorocyclobutyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,3-Difluorocyclobutyl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiaz-
olo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((3-methyloxetan-3-yl)methyl)-4,5,6,-
7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyra-
zolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Cyclopropyl-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6-
,7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6-
,7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-(Methoxymethyl)cyclopropyl)methyl)-N-(5-methyl-1,2,4-thiadiazol-3-y-
l)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,3-Difluoro
cyclobutyl)methyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3,3-Difluorocyclobutyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Cyclopropoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Ethoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-Methoxypropan-2-yl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-amine N-(4-M
ethoxypyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((3-methyloxetan-3-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(Cyclobutylmethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine
6-Cyclopropyl-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4--
b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-(Methoxymethyl)cyclopropyl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3,3-Difluorocyclobutyl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3,3-Difluorocyclobutyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Cyclopropoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Ethoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(1-Methoxypropan-2-yl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-(methoxymethyl)cyclopropyl)methyl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-Cyclopropyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-2-amine
6-(2-Ethoxyethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxypropyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-
-b]thiazolo[4,5-d]azepin-2-amine
6-Cyclopropyl-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N.sup.2-(6-(Cyclopropylmethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[-
4,5-d]azepin-2-yl)pyrimidine-2,4-diamine
N.sup.2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-yl) pyrimidine-2,4-diamine
4-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)butan-2-one
6-(2-(Azetidin-1-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(5-fluoropyrimidin-2--
yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-2-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)--
4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
4-(2-(4-Methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)butan-2-one
6-(2-(Azetidin-1-yl)ethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(4-methylpyrimidin-2--
yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-imidazol-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Fluoropyridin-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Methylpyridin-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)--
4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
4-(2-(4-Methoxypyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)butan-2-one
6-(2-(Azetidin-1-yl)ethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydro
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(4-methoxypyrimidin-2-
-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((1-methyl-1H-imidazol-2-yl)methyl)-4,5,6,7-
-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Fluoropyridin-2-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-
-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methoxypyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-
-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
4-(2-(6-Methylpyridin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-d-
]azepin-6(7H)-yl)butan-2-one
6-(2-(Azetidin-1-yl)ethyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(6-methylpyridin-2-yl-
)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Methyl-1H-imidazol-2-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,-
7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,-
7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((3-Fluoropyridin-2-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tetrahy-
dropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(6-Methylpyridin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetrahy-
dropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(6-Methylpyridin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(6-Methylpyridin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and a
pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof and an N-oxide form
thereof.
14. A compound according to claims 1 to 11, wherein said compound
is selected from:
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-2-methylpropyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(1-methoxypropan-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-4(S)-tetrahydrofuran-2-yl)methyl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(6-Methylpyridin-2-yl)-6-4(S)-tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Methylisoxazol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoro-4-methylpyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-(methylamino)propyl)-4,5,6,8-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-1(S)-methyl-ethyl)-4,5,6,8-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
3-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)propan-1-ol
N-(5-Fluoropyrimidin-2-yl)-6-(2-(2-methoxyethoxy)ethyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Ethoxyethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-morpholinoethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(2-Fluoroethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-pyrazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-4,5,6,8-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-(methoxymethyl)pyridin-2-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and a
pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof and an N-oxide form
thereof.
15. A compound according to claims 1 to 11, wherein said compound
is selected from:
N-(5-Fluoropyrimidin-2-yl)-6-(3-(piperidin-1-yl)propyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(4-Methylpyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-4-
,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6-
,8-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-Fluoropropyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
4-(3-(2-((5-Fluoropyrimidin-2-yl)amino)-4,5-dihydropyrazolo[3,4-b]thiazol-
o[4,5-d]azepin-6(8H)-yl)propyl)thiomorpholine 1,1-dioxide
N-(4-Methylpyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
6-(3-(3,5-Dimethylmorpholino)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
trihydrochloride
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
monohydrochloride
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine dihydrochloride dihydrate
and a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof and an N-oxide
form thereof.
16. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claims 1 to 15 and a
pharmaceutically acceptable carrier and/or excipient.
17. A method of treating or preventing a condition in a mammal,
including a human, the treatment or prevention of which is affected
or facilitated by the neuromodulatory effect of mGluR.sub.4
allosteric modulators, comprising administering to a mammal in need
of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
18. A method of treating or preventing a condition in a mammal,
including a human, the treatment or prevention of which is affected
or facilitated by the neuromodulatory effect of mGluR.sub.4
positive allosteric modulators, comprising administering to a
mammal in need of such treatment or prevention, an effective amount
of a compound/composition according to claims 1 to 16.
19. A method useful for treating or preventing central nervous
system disorders selected from the group consisting of: addiction,
tolerance or dependence; affective disorders, such as depression
and anxiety; psychiatric disease such as psychotic disorders,
attention-deficit/hyperactivity disorder and bipolar disorder;
Parkinson's disease, memory impairment, Alzheimer's disease,
dementia, delirium tremens, other forms of neurodegeneration,
neurotoxicity, and ischemia, comprising administering to a
mammalian patient in need of such treatment or prevention, an
effective amount of a compound/composition according to claims 1 to
16.
20. A method useful for treating or preventing central nervous
system disorders selected from the group consisting of: Parkinson's
disease and movement disorders such as bradykinesia, rigidity,
dystonia, drug-induced parkinsonism, dyskinesia, tardive
dyskinesia, L-DOPA-induced dyskinesia, dopamine agonist-induced
dyskinesia, hyperkinetic movement disorders, Gilles de la Tourette
syndrome, resting tremor, action tremor, akinesia, akinetic-rigid
syndrome, akathisia, athetosis, asterixis, tics, postural
instability, postencephalitic parkinsonism, muscle rigidity, chorea
and choreaform movements, spasticity, myoclonus, hemiballismus,
progressive supranuclear palsy, restless legs syndrome, and
periodic limb movement disorder, comprising administering to a
mammalian patient in need of such treatment or prevention, an
effective amount of a compound/composition according to claims 1 to
16.
21. A method of claim 20 comprising administering to a mammalian
patient in need of such treatment or prevention, an effective
amount of a compound/composition according to claims 1 to 13 in
combination with an agent selected from the group consisting of:
levodopa, levodopa with a selective extracerebral decarboxylase
inhibitor, carbidopa, entacapone, a COMT inhibitor, a dopamine
agonist, an anticholinergic, a cholinergic agonist, an NMDA
receptor antagonist, an MAO-B inhibitor, an mGluR.sub.5 antagonist,
an A.sub.2A antagonist, a butyrophenone neuroleptic agent, a
diphenylbutylpiperidine neuroleptic agent, a heterocyclic
dibenzazepine neuroleptic agent, an indo lone neuroleptic agent, a
phenothiazine neuroleptic agent or a thioxanthene neuroleptic
agent.
22. A method useful for treating or preventing central nervous
system disorders selected from the group consisting of: cognitive
disorders such as delirium, substance-induced persisting delirium,
dementia, dementia due to HIV disease, dementia due to Huntington's
disease, dementia due to Parkinson's disease, Parkinsonian-ALS
demential complex, dementia of the Alzheimer's type,
substance-induced persisting dementia, and mild cognitive
impairment, comprising administering to a mammalian patient in need
of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
23. A method useful for treating affective disorders selected from
the group consisting of: anxiety, agoraphobia, generalized anxiety
disorder (GAD), obsessive-compulsive disorder (OCD), panic
disorder, posttraumatic stress disorder (PTSD), social phobia,
other phobias, substance-induced anxiety disorder, and acute stress
disorder, comprising administering to a mammalian patient in need
of such treatment, an effective amount of a compound/composition
according to claims 1 to 16.
24. A method useful for treating or preventing central nervous
system disorders selected from the group consisting of: mood
disorders, bipolar disorders (I & II), cyclothymic disorder,
depression, dysthymic disorder, major depressive disorder, and
substance-induced mood disorder, comprising administering to a
mammalian patient in need of such treatment or prevention, an
effective amount of a compound/composition according to claims 1 to
16.
25. A method useful for treating or preventing neurological
disorders selected from the group consisting of: neurodegeneration,
neurotoxicity or ischemia such as stroke, spinal cord injury,
cerebral hypoxia, intracranial hematoma, Parkinson's disease,
memory impairment, Alzheimer's disease, dementia, and delirium
tremens, comprising administering to a mammalian patient in need of
such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
26. A method useful for treating or preventing inflammatory central
nervous system disorders selected from the group consisting of:
multiple sclerosis forms such as benign multiple sclerosis,
relapsing-remitting multiple sclerosis, secondary progressive
multiple sclerosis, primary progressive multiple sclerosis, and
progressive-relapsing multiple sclerosis, comprising administering
to a mammalian patient in need of such treatment or prevention, an
effective amount of a compound/composition according to claims 1 to
16.
27. A method useful for treating or preventing migraine, comprising
administering to a mammalian patient in need of such treatment or
prevention, an effective amount of a compound/composition according
to claims 1 to 16.
28. A method useful for treating or preventing epilepsy and tremor,
temporal lobe epilepsy, epilepsy secondary to another disease or
injury such as chronic encephalitis, traumatic brain injury, stroke
or ischemia, comprising administering to a mammalian patient in
need of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
29. A method useful for treating or preventing central nervous
system disorders selected from the group consisting of psychotic
disorders: schizophrenia, delusional disorder, schizoaffective
disorder, schizophreniform disorder, substance-induced psychotic
disorder, comprising administering to a mammal in need of such
treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
30. A method useful for treating or preventing inflammation and/or
neurodegeneration resulting from traumatic brain injury, stroke,
ischemia, spinal cord injury, cerebral hypoxia or intracranial
hematoma, comprising administering to a mammalian patient in need
of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
31. A method useful for treating or preventing sensory, motor or
cognitive symptoms resulting from traumatic brain injury, stroke,
ischemia, spinal cord injury, cerebral hypoxia or intracranial
hematoma, comprising administering to a mammalian patient in need
of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
32. A method useful for treating medulloblastomas, comprising
administering to a mammalian patient in need of such treatment, an
effective amount of a compound/composition according to claims 1 to
16.
33. A method useful for treating or preventing inflammatory or
neuropathic pain, comprising administering to a mammalian patient
in need of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
34. A method useful for treating, preventing, ameliorating,
controlling or reducing the risk of various metabolic disorders
associated with glutamate dysfunction, comprising administering to
a mammalian patient in need of such treatment, prevention,
amelioration or control of the risk, an effective amount of a
compound/composition according to claims 1 to 16.
35. A method useful for treating or preventing type 2 diabetes,
comprising administering to a mammalian patient in need of such
treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
36. A method useful for treating or preventing diseases or
disorders of the retina, retinal degeneration or macular
degeneration, comprising administering to a mammalian patient in
need of such treatment or prevention, an effective amount of a
compound/composition according to claims 1 to 16.
37. A method useful for treating or preventing diseases or
disorders of the gastrointestinal tract including gastro-esophageal
reflux disease (GERD), lower esophageal sphincter diseases or
disorders, diseases of gastrointestinal motility, colitis, Crohn's
disease or irritable bowel syndrome (IBS), comprising administering
to a mammalian patient in need of such treatment or prevention, an
effective amount of a compound/composition according to claims 1 to
16.
38. Use of a compound according to claims 1 to 15 in the
manufacture of a medicament for a use as defined in any of claims
17 to 37.
39. Use of a compound according to claims 1 to 15 to prepare a
tracer for imaging a metabotropic glutamate receptor.
40. Use of a compound according to claims 1 to 15 as a taste agent,
flavour agent, flavour enhancing agent or a food or beverage
additive.
41. A compound according to claims 1 to 15 or a composition
according to claim 16 for a use in a treatment or prevention as
defined in any of claims 17 to 22, 24 to 31, 33 and 35 to 37.
42. A compound according to claims 1 to 15 or a composition
according to claim 16 for a use as defined in claim 34.
43. A compound according to claims 1 to 15 or a composition
according to claim 16 for a use in a treatment as defined in any of
claims 23 and 32.
44. A compound according to any one of claims 1 to 15 in
combination with levodopa for treating or preventing a condition as
defined in claim 20.
45. A compound according to any one of claims 1 to 15 in
combination with a dopamine agonist for treating or preventing a
condition as defined in claim 20.
46. A compound according to any one of claims 1 to 15 in
combination with an A.sub.2A antagonist for treating or preventing
a condition as defined in claim 20.
Description
SUMMARY OF THE INVENTION
##STR00002##
[0002] The present invention relates to novel compounds of Formula
(I), wherein M and R' are defined as in Formula (I); invention
compounds are modulators of metabotropic glutamate
receptors--subtype 4 ("mGluR.sub.4") which are useful for the
treatment or prevention of central nervous system disorders as well
as other disorders modulated by mGluR.sub.4 receptors. The
invention is also directed to pharmaceutical compositions and the
use of such compounds in the manufacture of medicaments, as well as
to the use of such compounds for the prevention and treatment of
such diseases in which mGluR.sub.4 is involved.
BACKGROUND OF THE INVENTION
[0003] Glutamate is the major amino-acid transmitter in the
mammalian central nervous system (CNS). Glutamate plays a major
role in numerous physiological functions, such as learning and
memory but also sensory perception, development of synaptic
plasticity, motor control, respiration and regulation of
cardiovascular function.
[0004] Furthermore, glutamate is at the center of several different
neurological and psychiatric diseases, where there is an imbalance
in glutamatergic neurotransmission.
[0005] Glutamate mediates synaptic neurotransmission through the
activation of ionotropic glutamate receptor channels (iGluRs),
namely the NMDA, AMPA and kainate receptors which are responsible
for fast excitatory transmission (Nakanishi S. et al., (1998) Brain
Res. Rev., 26(2-3):230-235).
[0006] In addition, glutamate activates metabotropic glutamate
receptors (mGluRs) which have a more modulatory role that
contributes to the fine-tuning of synaptic efficacy.
[0007] The mGluRs are G protein-coupled receptors (GPCRs) with
seven-transmembrane spanning domains and belong to GPCR family 3
along with the calcium-sensing, GABAb and pheromone receptors.
[0008] The mGluR family is composed of eight members. They are
classified into three groups (group I comprising mGluR.sub.1 and
mGluR.sub.5; group II comprising mGluR.sub.2 and mGluR.sub.3; group
III comprising mGluR.sub.4, mGluR.sub.6, mGluR.sub.7 and
mGluR.sub.8) according to sequence homology, pharmacological
profile and nature of intracellular signalling cascades activated
(Schoepp D. D. et al., (1999) Neuropharmacology,
38(10):1431-1476).
[0009] Glutamate activates the mGluRs through binding to the large
extracellular amino-terminal domain of the receptor, herein called
the orthosteric binding site. This activation induces a
conformational change of the receptor which results in the
activation of the G-protein and intracellular signalling
pathways.
[0010] In the central nervous system, mGluR.sub.4 receptors are
expressed most intensely in the cerebellar cortex, basal ganglia,
sensory relay nuclei of the thalamus and hippocampus (Bradley et
al., (1999) Journal of Comparative Neurology, 407:33-46; Corti et
al., (2002) Neuroscience, 110:403-420). The mGluR.sub.4 subtype is
negatively coupled to adenylate cyclase via activation of the Gaio
protein, is expressed primarily on presynaptic terminals,
functioning as an autoreceptor or heteroceptor and activation of
mGluR.sub.4 leads to decreases in transmitter release from
presynaptic terminals (Corti et al., (2002) Neuroscience,
110:403-420; Millan et al., (2002) Journal of Biological Chemistry,
277:47796-47803; Valenti et al., (2003) Journal of Neuroscience,
23:7218-7226).
[0011] Orthosteric agonists of mGluR.sub.4 are not selective and
activate the other Group III mGluRs (Schoepp et al., (1999)
Neuropharmacology, 38:1431-1476). The Group III orthosteric agonist
L-AP4 (L-2-amino-4-phosphonobutyrate) was able to reduce motor
deficits in animal models of Parkinson's disease (Valenti et al.,
(2003) J. Neurosci., 23:7218-7226) and decrease excitotoxicity
(Bruno et al., (2000) J. Neurosci., 20:6413-6420) and these effects
appear to be mediated through mGluR.sub.4 (Marino et al., (2005)
Curr. Topics Med. Chem., 5:885-895). In addition to L-AP4, ACPT-1,
another selective group III mGluR agonist has been shown to caused
a dose and structure-dependent decrease in haloperidol-induced
catalepsy and attenuated haloperidol-increased Proenkephalin mRNA
expression in the striatum (Konieczny et al., (2007) Neuroscience,
145:611-620). Furthermore, Lopez et al. (2007, J. Neuroscience,
27:6701-6711) have shown that bilateral infusions of ACPT-I or
L-AP4 into the globus pallidus fully reversed the severe akinetic
deficits produced by 6-hydroxydopamine lesions of nigrostriatal
dopamine neurons in a reaction-time task without affecting the
performance of controls. In addition, the reversal of
haloperidol-induced catalepsy by intrapallidal ACPT-1 was prevented
by concomitant administration of a selective group III receptor
antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. The
opposite effects produced by group III mGluR activation in the SNr
strongly suggest a role of mGluR.sub.4 rather than other mGluR
receptor sub-types in normalizing basal ganglia activity (Lopez et
al. 2007).
[0012] These results suggest that, among mGluR subtypes,
mGluR.sub.4 is believed to be the most interesting novel drug
target for the treatment of Parkinson's disease (for a review, see
Conn et al., (2005) Nature Review Neuroscience,
.delta.:787-798).
[0013] Symptoms of Parkinson's disease appear to be due to an
imbalance in the direct and indirect output pathways of the basal
ganglia, and reduction of transmission at the inhibitory GABAergic
striato-pallidal synapse in the indirect pathway may result in
alleviation of these symptoms (Marino et al., (2002) Amino Acids,
23:185-191).
[0014] mGluR.sub.4 is more abundant in striato-pallidal synapses
than in striato-nigral synapses, and its localization suggests
function as a presynaptic heteroreceptor on GABAergic neurons
(Bradley et al., (1999) Journal of Comparative Neurology,
407:33-46) suggesting that selective activation or positive
modulation of mGluR.sub.4 would decrease GABA release in this
synapse thereby decreasing output of the indirect pathway and
reducing or eliminating the Parkinson's disease symptoms. Classical
treatment of Parkinsonism typically involves the use of levodopa
combined with carbidopa (SINEMET.TM.) or benserazide (MADOPAR.TM.).
Dopamine agonists such as bromocriptine (PARLODEL.TM.), lisuride
and pergolide (CELANCE.TM.) act directly on dopamine receptors and
are also used for the treatment of Parkinsonism. These molecules
have the same side-effect profile as levodopa.
[0015] A new avenue for developing selective compounds acting at
mGluRs is to identify molecules that act through allosteric
mechanisms, modulating the receptor by binding to a site different
from the highly conserved orthosteric binding site.
[0016] Positive allosteric modulators of mGluRs have emerged
recently as novel pharmacological entities offering this attractive
alternative. This type of molecule has been discovered for
mGluR.sub.1, mGluR.sub.2, mGluR.sub.4, mGluR.sub.5, mGluR.sub.7 and
mGluR.sub.8 (Knoflach F. et al. (2001) Proc. Natl. Acad. Sci. USA,
98:13402-13407; Johnson M. P. et al., (2002) Neuropharmacology,
43:799-808; O'Brien J. A. et al., (2003) Mol. Pharmacol.,
64:731-740; Johnson M. P. et al., (2003) J. Med. Chem.,
46:3189-3192; Marino M. J. et al., (2003) Proc. Natl. Acad. Sci.
USA, 100:13668-13673; Mitsukawa K. et al., (2005) Proc. Natl. Acad.
Sci. USA, 102(51):18712-18717; Wilson J. et al., (2005)
Neuropharmacology, 49:278; for a review see Mutel V., (2002) Expert
Opin. Ther. Patents, 12:1-8; Kew J. N., (2004) Pharmacol. Ther.,
104(3):233-244; Johnson M. P. et al., (2004) Biochem. Soc. Trans.,
32:881-887; recently Ritzen A., Mathiesen, J. M. and Thomsen C.,
(2005) Basic Clin. Pharmacol. Toxicol., 97:202-213).
[0017] In particular molecules have been described as mGluR.sub.4
positive allosteric modulators (Maj et al., (2003)
Neuropharmacology, 45:895-906; Mathiesen et al., (2003) British
Journal of Pharmacology, 138:1026-1030). It has been demonstrated
that such molecules have been characterized in in vitro systems as
well as in rat brain slices where they potentiated the effect of
L-AP4 in inhibiting transmission at the striatopallidal synapse.
These compounds do not activate the receptor by themselves (Marino
et al., (2003) Proc. Nat. Acad. Sci. USA, 100:13668-13673). Rather,
they enable the receptor to produce a maximal response to a
concentration of glutamate or the Group III orthosteric agonist
L-AP4 which by itself induces a minimal response.
[0018] PHCCC
(N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide), a
positive allosteric modulator of mGluR.sub.4 not active on other
mGluRs (Maj et al., (2003) Neuropharmacology, 45:895-906), has been
shown to be efficacious in animal models of Parkinson's disease
thus representing a potential novel therapeutic approach for
Parkinson's disease as well as for other motor disorders and
disturbances (Marino et al., (2003) Proc. Nat. Acad. Sci. USA,
100:13668-13673), neurodegeneration in Parkinson's disease (Marino
et al., (2005) Curr. Topics Med. Chem., 5:885-895; Valenti et al.,
(2005) J. Pharmacol. Exp. Ther., 313:1296-1304; Vernon et al.,
(2005) Eur. J. Neurosci., 22:1799-1806, Battaglia et al., (2006) J.
Neurosci., 26:7222-7229), and neurodegeneration in Alzheimer's
disease or due to ischemic or traumatic insult (Maj et al., (2003)
Neuropharmacology, 45:895-906).
[0019] PHCCC also has been shown to be active in an animal model of
anxiety (Stachowicz et al., (2004) Eur. J. Pharmacol.,
498:153-156). Previously, ACPT-1 has been shown to produce a
dose-dependent anti-conflict effect after intrahippocampal
administration and anti-depressant-like effects in rats after
intracerebroventricular administration (Tatarczynska et al., (2002)
Pol. J. Pharmacol., 54(6):707-710). More recently, ACPT-1 has also
been shown to have anxiolytic-like effects in the stress-induced
hyperthermia, in the elevated-plus maze in mice and in the Vogel
conflict test in rats when injected intraperitoneally (Stachowicz
et al., (2009) Neuropharmacology, 57(3):227-234).
[0020] Activation of mGluR.sub.4 receptors which are expressed in
.alpha.- and F-cells in the islets of Langerhans inhibits glucagon
secretion. Molecules which activate or potentiate the agonist
activity of these receptors may be an effective treatment for
hyperglycemia, one of the symptoms of type 2 diabetes (Uehara et
al., (2004) Diabetes, 53:998-1006).
[0021] The .beta.-chemokine RANTES is importantly involved in
neuronal inflammation and has been implicated in the
pathophysiology of multiple sclerosis (MS). Activation of Group III
mGluRs with L-AP4 reduced the synthesis and release of RANTES in
wild-type cultured astrocytes, whereas the ability of L-AP4 to
inhibit RANTES was greatly decreased in astrocyte cultures from
mGluR.sub.4 knockout mice (Besong et al., (2002) Journal of
Neuroscience, 22:5403-5411). A high amount of glutamate is found in
the brain of patients with MS and glutamate, in addition to
inflammatory cytokines, is a major contributor to neurodegeneration
in MS (Stover J. F. et al. (1997) Eur. J. Clin. Invest.
27:1038-1043; Srinivasan R. et al. (2005) Brain, 128:1016-1025;
Frigo M. et al. (2012) Current Med. Chem. 19:1295-1299).
Experimental autoimmune encephalomyelitis (EAE) is an animal model
of brain inflammation and is an animal model of the human CNS
demyelinating diseases, including the diseases multiple sclerosis
and acute disseminated encephalomyelitis (ADEM). Repeated
administration of PHCCC in the myelin oligodendrocyte glycoprotein
(MOG) induced EAE model showed attenuated disease in wildtype mice
(Fallarino et al., (2010) Nature Medicine, 16:897-902). PHCCC also
reduced the number of relapses and their severity when
administrated after the first attack in a mice model of
relapsing-remitting-EAE (RR-EAE) model of MS. These data suggest
that positive allosteric modulators of mGluR.sub.4 may be an
effective treatment for neuroinflammatory disorders of the central
nervous system, including multiple sclerosis and related
disorders.
[0022] Glutamate receptors play a critical role in the pain pathway
and the role of mGluR4 has been demonstrated in several studies
(Goudet C. et al. (2009) Brain Res. Rev., 60:43-56; (2008) Pain,
137:112-24). Goudet et al. demonstrated that both the agonist
ACPT-1 and mGluR4 PAM (-)-PHCCC were able to dose dependently
inhibit the mechanical hypersensitivity associated with different
pathological pain states when administered intrathecally. ACPT-1
demonstrated efficacy in the rat formalin test and against the
mechanical hyperalgesia elicited in inflammatory pain models and
neuropathic pain models. (-)-PHCCC showed efficacy in both the
chronic constriction injury model (CCI) and vincristine-induced
peripheral neuropathy rat models. Similar results were obtained
using the allosteric agonist VU0155041, which dose dependently
attenuated hyperalgesia in rat neuropathic pain model (Wang H. et
al. (2011) NeuroReport, 22:244-248). Thus, positive allosteric
modulators of mGluR.sub.4 may be useful as new agents for the
treatment of pain or related disorders.
[0023] Recent studies using Group III mGluR orthosteric agonists
showed evidence of their involvement in schizophrenia as observed
in rodent model of psychosis. Orthosteric mGluR.sub.4 agonist
LSP1-2111 showed antipsychotic-like activity in relevant models for
positive symptoms of psychosis, producing a dose-dependent reversal
of both MK-801- and amphetamine-induced hyperactivities in rodents.
mGluR.sub.4/8 preferred agonists ACPT-1 (Palucha-Poniewiera et al.,
(2008) Neuropharmacology, 55:517-24) and LSP1-2111 dose dependently
inhibited 5-HT.sub.2A agonist DOI-induced head twitches in mice, a
serotonergic relevant model for psychosis and hallucination
(Wieronska et al., (2012) Psychopharmacology, 220(3):481-494).
These results represent strong evidence for additional therapeutic
use of mGluR.sub.4 activators as potential antipsychotic drugs.
[0024] Two different variants of the mGluR.sub.4 receptor are
expressed in taste tissues and may function as receptors for the
umami taste sensation (Monastyrskaia et al., (1999) Br. J
Pharmacol., 128:1027-1034; Toyono et al., (2002) Arch. Histol.
Cytol., 65:91-96). Thus positive allosteric modulators of
mGluR.sub.4 may be useful as taste agents, flavour agents, flavour
enhancing agents or food additives.
[0025] There is anatomical evidence that the majority of vagal
afferents innervating gastric muscle express group III mGluRs
(mGluR.sub.4, mGluR.sub.6, mGluR.sub.7 and mGluR.sub.8) and
actively transport receptors to their peripheral endings (Page et
al., (2005) Gastroenterology, 128:402-10). Recently, it was shown
that the activation of peripheral group III mGluRs inhibited vagal
afferent mechanosensitivity in vitro which translates into reduced
triggering of transient lower esophageal sphincter relaxations and
gastroesophageal reflux in vivo (Young et al., (2008)
Neuropharmacol, 54:965-975). Labelling for mGluR.sub.4 and
mGluR.sub.8 was abundant in gastric vagal afferents in the nodose
ganglion, at their termination sites in the nucleus tractus
solitarius and in gastric vagal motorneurons. These data suggest
that positive allosteric modulators of mGluR.sub.4 may be an
effective treatment for gastroesophageal reflux disease (GERD) and
lower esophageal disorders and gastro-intestinal disorders.
[0026] International patent publication WO2005007096 has described
mGluR.sub.4 receptor positive allosteric modulators useful, alone
or in combination with a neuroleptic agent, for treating or
preventing movement disorders. However, none of the specifically
disclosed compounds are structurally related to the compounds of
the invention.
[0027] Recently, new mGluR.sub.4 receptor positive allosteric
modulators have been described: pyrazolo[3,4-d]pyrimidine
derivatives (Niswender et al., (2008) Bioorganic & Medicinal
Chemistry Letters, 18(20):5626-5630), functionalized benzylidene
hydrazinyl-3-methylquinazoline and
bis-2,3-dihydroquinazolin-4(1H)-one (Williams et al., (2009)
Bioorganic & Medicinal Chemistry Letters, 19:962-966) and
heterobiarylamides (Engers et al., (2009) Journal of Medicinal
Chemistry, 52 (14):4115-4118). Niswender et al. (2008) Molecular
Pharmacology, 74(5):1345-1358), described
(.+-.)-cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexane carboxylic
acid as a positive allosteric modulator of mGluR.sub.4 also having
agonist activity. This moderately active molecule has demonstrated
evidence of efficacy following icy injection in rat models of
Parkinson's disease. International patent publications WO2009010454
and WO2009010455 have mentioned amido derivatives and novel
heteroaromatic derivatives, respectively, as positive allosteric
modulators of metabotropic glutamate receptors. The subject of the
latter case has been examined in the following article: East
Stephen P. et al., (2010) Expert Opin. Ther. Patents,
20(3):441-445. Finally, Williams R. et al., described in (2010) ACS
Chemical Neuroscience, 1(6):411-419, the "Re-exploration of the
PHCCC scaffold".
[0028] International patent publication WO2010079238 and
WO2012009001 have described novel tricyclic heteroaromatic
derivatives and their use as positive allosteric modulators of
mGluRs. More recently, a review on recent progress on the
identification of metabotropic glutamate 4 receptor ligands and
their potential utility as CNS therapeutics (Robichaud A. et al.,
(2011) ACS Chem. Neuroscience, 2:433-49) has cited some of the
examples described in the WO2010079238 patent application; Hong
S.-P et al., (2011) J. Med. Chem., 54(14):5070-5081, have described
tricyclic thiazolopyrazole derivatives as metabotropic glutamate
receptor 4 positive allosteric modulators.
[0029] The present inventors have discovered novel thiazole
compounds of general Formula (I) which, surprisingly, show potent
activity and selectivity on the mGluR.sub.4 receptor. The compounds
of the invention demonstrate advantageous properties over compounds
of the prior art. Improvements have been observed in one or more of
the following characteristics of the compounds of the invention:
the potency on the target, the selectivity for the target, the
pharmacokinetic, the brain penetration, and the activity in
behavioural models.
[0030] Such aminothiazole derivatives are useful for treating or
preventing a condition in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of mGluR.sub.4 modulators.
[0031] In the case of the treatment of movement disorders such as
Parkinson's Disease, the compounds of the invention can be used
alone or in combination with an agent selected from the group
consisting of: a dopamine precursor such as levodopa, melevodopa
and etilevodopa, levodopa with a selective extracerebral
decarboxylase inhibitor such as carbidopa and benserazide, a
catechol-O-methyl transferase (COMT) inhibitor such as entacapone
and tolcapone, a dopamine agonist such as pramipexole, ropinorole,
apomorphine, rotigotine, bromocriptine cabergoline and pergolide, a
monoamine oxidase B (MAO-B) inhibitor such as selegiline and
rasagiline, an anticholinergic agent such as benztropine,
trihexyphenidyl, procyclidine and biperiden, a glutamate (NMDA)
blocking drug such as amantadine, an adenosine A.sub.2a antagonist
such as istradefylline and preladenant, an alpha-2 adrenergic
antagonist such as atipamezole or fipamezole, a 5-HT.sub.1A agonist
such as piclozotan or a 5-HT.sub.1A/.sub.1B partial agonist such as
eltoprazine. Finally, in the case of the treatment of iatrogenic
movement disorders, the compounds of the invention can be used in
combination with an agent selected from the group of: a
butyrophenone neuroleptic agent, a diphenylbutylpiperidine
neuroleptic agent, a heterocyclic dibenzazepine neuroleptic agent,
an indolone neuroleptic agent, a phenothiazine neuroleptic agent or
a thioxanthene neuroleptic agent
DETAILED DESCRIPTION OF THE INVENTION
[0032] The invention relates to compounds having metabotropic
glutamate receptor 4 modulator activity. In its most general
compound aspect, the present invention provides a compound
according to Formula (I),
##STR00003##
[0033] a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof and an N-oxide
form thereof, wherein:
[0034] M is an optionally substituted heteroaryl;
[0035] R.sup.1 is hydrogen or an optionally substituted radical
selected from the group of --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.1-C.sub.6)alkylene-aryl, aryl,
--(C.sub.1-C.sub.6)alkylene-heteroaryl, heteroaryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-OR.sup.2,
--(C.sub.2-C.sub.6)alkylene-NR.sup.2R.sup.3,
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--NR.sup.2R.sup.3,
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.2;
[0036] R.sup.2 and R.sup.3 are each independently hydrogen or an
optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N--((C.sub.0-C.sub.6)alkyl).sub.2;
[0037] R.sup.2 and R.sup.3 may be taken together to form an
optionally substituted 3 to 10 membered carbocyclic or heterocyclic
ring; and
[0038] provided that the compound is not: [0039]
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0040]
6-(2-Methoxyethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0041]
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0042]
6-(1-Methoxypropan-2-yl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0043]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0044]
6-(2-Methoxyethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine [0045]
N-(6-Fluoropyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine [0046]
N-(5-Fluoropyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine [0047]
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0048]
N,N-Dimethyl-2-(2-(4-methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-6(8H)-yl)acetamide [0049]
6-(2-Methoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0050]
6-(2-Methoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,8-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0051]
2-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)ethanol [0052]
N.sup.2-(6-(2-Methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-yl) pyridine-2,6-diamine [0053]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0054]
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0055]
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0056]
N-(5-Fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine [0057]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0058]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0059]
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydrofuran-3-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0060]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(methylamino)ethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0061]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxypropyl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0062]
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0063]
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0064]
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0065]
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0066]
6-(Cyclopropylmethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0067]
6-(Cyclopropylmethyl)-N-(6-fluoropyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0068]
64(5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0069]
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0070]
N-(5-Fluoropyrimidin-2-yl)-6-(2-isopropoxyethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0071]
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0072]
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine [0073]
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0074]
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0075]
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0076]
2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]aze-
pin-2-ylamino)pyrimidin-5-ol [0077]
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0078]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0079]
(6-(6-(2-Methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]az-
epin-2-ylamino)pyridin-2-yl)methanol [0080]
6-(2-Methoxyethyl)-N-(2-methylpyrimidin-4-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0081]
6-(2-Methoxyethyl)-N-(pyrimidin-4-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]th-
iazolo[4,5-d]azepin-2-amine [0082]
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0083]
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0084]
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0085]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0086]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0087]
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0088]
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0089]
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0090]
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0091]
N-(5-Fluoropyrimidin-2-yl)-6-phenethyl-4,5,6,7-tetrahydropyrazolo[3,4-b]t-
hiazolo[4,5-d]azepin-2-amine [0092]
N-(3-Fluoro-6-methylpyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0093]
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0094]
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile [0095]
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0096]
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0097]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(pyridin-2-yl)ethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0098]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0099]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0100]
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0101]
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0102]
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile [0103]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0104]
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0105]
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0106]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0107]
6-(1-(5-Chloropyridin-2-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0108]
6-Cyclobutyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]-
thiazolo[4,5-d]azepin-2-amine and [0109]
N-(6-(Fluoromethyl)pyridin-2-yl)-6-(2-methoxyethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
[0110] In another aspect of Formula (I), the invention provides a
compound according to Formula (II):
##STR00004##
[0111] a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof and an N-oxide
form thereof, wherein:
[0112] (A).sub.m are each independently selected from the group of
hydrogen, halogen, --CN, --OH, --CF.sub.3, --OCF.sub.3, --NH.sub.2
and an optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.4,
--(C.sub.0-C.sub.6)alkylene-NR.sup.4R.sup.5 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.4;
[0113] m is an integer ranging from 1 to 2;
[0114] R.sup.4 and R.sup.5 are each independently hydrogen or an
optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N--((C.sub.0-C.sub.6)alkyl).sub.2;
and
[0115] provided that the compound is not: [0116]
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0117]
6-(2-Methoxyethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0118]
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0119]
6-(1-Methoxypropan-2-yl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0120]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0121]
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0122]
N,N-Dimethyl-2-(2-(4-methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-6(8H)-yl)acetamide [0123]
6-(2-Methoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0124]
2-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)ethanol [0125]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0126]
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0127]
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0128]
N-(5-Fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine [0129]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0130]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0131]
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydrofuran-3-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0132]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(methylamino)ethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0133]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxypropyl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0134]
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0135]
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0136]
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0137]
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0138]
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0139]
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0140]
N-(5-Fluoropyrimidin-2-yl)-6-(2-isopropoxyethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0141]
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0142]
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine [0143]
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0144]
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0145]
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0146]
2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]aze-
pin-2-ylamino)pyrimidin-5-ol [0147]
N-(5-Fluoropyrimidin-2-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0148]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0149]
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0150]
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0151]
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0152]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0153]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0154]
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0155]
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0156]
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0157]
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0158]
N-(5-Fluoropyrimidin-2-yl)-6-phenethyl-4,5,6,7-tetrahydropyrazolo[3,4-b]t-
hiazolo[4,5-d]azepin-2-amine [0159]
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0160]
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile [0161]
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0162]
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0163]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(pyridin-2-yl)ethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0164]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0165]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0166]
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0167]
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0168]
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile [0169]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0170]
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0171]
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0172]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0173]
6-(1-(5-Chloropyridin-2-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and [0174]
6-Cyclobutyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]-
thiazolo[4,5-d]azepin-2-amine.
[0175] In another aspect of Formula (I), the invention provides a
compound according to Formula (III):
##STR00005##
[0176] a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof and an N-oxide
form thereof, wherein:
[0177] Q is an optionally substituted aryl, heteroaryl, heterocycle
or cycloalkyl;
[0178] (B) are each independently selected from the group of
hydrogen, halogen, --CN, --OH, --CF.sub.3, --OCF.sub.3, --NH.sub.2
and an optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.6,
--(C.sub.0-C.sub.6)alkylene-NR.sup.6R.sup.7 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.6;
[0179] n is an integer ranging from 1 to 2;
[0180] R.sup.6 and R.sup.7 are each independently hydrogen or an
optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cyclo alkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N--((C.sub.0-C.sub.6)alkyl).sub.2;
and
[0181] provided that the compound is not: [0182]
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0183]
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0184]
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0185]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0186]
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0187]
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0188]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0189]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0190]
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0191]
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0192]
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0193]
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0194]
6-(Cyclopropylmethyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0195]
6-(Cyclopropylmethyl)-N-(6-fluoropyridin-2-yl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0196]
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0197]
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0198]
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0199]
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine [0200]
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0201]
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0202]
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0203]
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0204]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0205]
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0206]
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0207]
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0208]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0209]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0210]
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0211]
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0212]
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0213]
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0214]
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0215]
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile [0216]
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0217]
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0218]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0219]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0220]
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0221]
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0222]
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile [0223]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0224]
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0225]
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and [0226]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
[0227] In another aspect of Formula (III), the invention provides a
compound according to Formula (IV):
##STR00006##
[0228] a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof and an N-oxide
form thereof, wherein:
[0229] (A).sub.m are each independently selected from the group of
hydrogen, halogen, --CN, --OH, --CF.sub.3, --OCF.sub.3, --NH.sub.2
and an optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, --(C.sub.0-C.sub.6)alkylene-OR.sup.4,
--(C.sub.0-C.sub.6)alkylene-NR.sup.4R.sup.5 and
--(C.sub.0-C.sub.6)alkylene-C(.dbd.O)--R.sup.4;
[0230] m is an integer ranging from 1 to 2; and
[0231] R.sup.4 and R.sup.5 are each independently hydrogen or an
optionally substituted radical selected from the group of
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)cyanoalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkylene-(C.sub.1-C.sub.6)alkyl,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkyl, heteroaryl, --(C.sub.1-C.sub.6)alkylene-heteroaryl, aryl,
--(C.sub.1-C.sub.6)alkylene-aryl,
--(C.sub.1-C.sub.6)alkylene-heterocycle, heterocycle,
--(C.sub.2-C.sub.6)alkylene-O--(C.sub.0-C.sub.6)alkyl and
--(C.sub.2-C.sub.6)alkylene-N--((C.sub.0-C.sub.6)alkyl).sub.2;
and
[0232] provided that the compound is not: [0233]
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0234]
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0235]
6-((1-Methyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0236]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methylisoxazol-3-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0237]
6-((3,5-Dimethylisoxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0238]
N-(5-Fluoropyrimidin-2-yl)-6-((2-isopropyloxazol-4-yl)methyl)-4,5,6,8-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0239]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0240]
N-(5-Fluoropyrimidin-2-yl)-6-(pyridin-4-ylmethyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0241]
N-(5-Fluoropyrimidin-2-yl)-6-((3-methylisoxazol-5-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0242]
6-(Cyclopentylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0243]
6-(Cyclopropylmethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0244]
6-(Cyclohexylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0245]
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0246]
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropylisoxazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0247]
6-(Cyclobutylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine [0248]
6-Benzyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thia-
zolo[4,5-d]azepin-2-amine [0249]
6-((3-Methylisoxazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0250]
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0251]
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0252]
N-(5-Fluoropyrimidin-2-yl)-6-4(R)-tetrahydrofuran-2-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0253]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0254]
6-((1H-Pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0255]
6-((4-Bromo-1H-pyrazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0256]
6-(4-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0257]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0258]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0259]
6-((5-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0260]
N-(5-Fluoropyrimidin-2-yl)-6-((5-(trifluoromethyl)pyridin-2-yl)methyl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0261]
N-(5-Fluoropyrimidin-2-yl)-6-((4-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine [0262]
6-((3-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0263]
6-(3-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0264]
4-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile [0265]
N-(5-Fluoropyrimidin-2-yl)-6-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0266]
N-(5-Fluoropyrimidin-2-yl)-6-((6-methylpyridin-2-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0267]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0268]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0269]
6-(2-Chlorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0270]
6-(4-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0271]
6-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)nicotinonitrile [0272]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methoxypyridin-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0273]
N-(5-Fluoropyrimidin-2-yl)-6-(piperidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0274]
6-((5-Chlorothiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine and [0275]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine.
[0276] In another aspect of Formula (III), the invention provides a
compound wherein:
[0277] M is selected from the group of formula:
##STR00007##
is selected from the group of formula:
##STR00008##
[0278] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (III).
[0279] In another aspect of Formula (III), the invention provides a
compound wherein:
[0280] M is:
##STR00009##
is selected from the group of formula:
##STR00010##
[0281] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (III).
[0282] In another aspect of Formula (I), the invention provides a
compound wherein:
[0283] M is selected from the group of formula:
##STR00011##
and R.sup.1 is selected from the group of formula:
##STR00012##
[0284] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (I).
[0285] In another aspect of Formula (I), the invention provides a
compound wherein:
[0286] M is:
##STR00013##
and R.sup.1 is selected from the group of formula:
##STR00014##
[0287] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (I).
[0288] In another aspect of Formula (I), the invention provides a
compound wherein:
[0289] M is:
##STR00015##
and R.sup.1 is selected from the group of formula:
##STR00016##
[0290] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (I).
[0291] In another aspect of Formula (III), the invention provides a
compound wherein:
[0292] M is:
##STR00017##
[0293] This aspect of the invention does not encompass any of the
compounds disclaimed in Formula (III).
[0294] Particular preferred compounds of the invention are
compounds as mentioned in the following list (List of Particular
Preferred Compounds), as well as a pharmaceutically acceptable acid
or base addition salt thereof, a stereochemically isomeric form
thereof and an N-oxide form thereof: [0295]
3-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)methyl)benzonitrile [0296]
6-(3-Fluorobenzyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0297]
6-(Cyclopropylmethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0298]
6-((5-Cyclopropylisoxazol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0299]
6-((2,3-Dihydrobenzofuran-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0300]
N-(5-Fluoropyrimidin-2-yl)-6-(3-(trifluoromethyl)benzyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0301]
6-((3-Cyclopropylisoxazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0302]
6-((2-Cyclopropylthiazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0303]
6-(1-Methoxypropan-2-yl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0304]
6-((5-Chloropyridin-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0305]
N-(5-Fluoropyrimidin-2-yl)-6-(3-methoxycyclobutyl)-4,5,6,7-tetrahydropyra-
zolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0306]
N-(5-Fluoropyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-
-b]thiazolo[4,5-d]azepin-2-amine [0307]
6-(3,3-Difluorocyclobutyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0308]
6-((3,3-Difluorocyclobutyl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0309]
N-(5-Fluoropyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0310]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiaz-
olo[4,5-d]azepin-2-amine [0311]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0312]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((3-methyloxetan-3-yl)methyl)-4,5,6,-
7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0313]
6-(Cyclobutylmethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0314]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyra-
zolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0315]
6-Cyclopropyl-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0316]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6-
,7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0317]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6-
,7-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0318]
6-((1-(Methoxymethyl)cyclopropyl)methyl)-N-(5-methyl-1,2,4-thiadiazol-3-y-
l)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0319] 6-(3,3-Difluoro
cyclobutyl)methyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0320]
6-(3,3-Difluorocyclobutyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0321]
N-(5-Methyl-1,2,4-thiadiazol-3-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0322]
6-(2-Cyclopropoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0323]
6-(2-Ethoxyethyl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0324]
6-(1-Methoxypropan-2-yl)-N-(5-methyl-1,2,4-thiadiazol-3-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0325]
N-(4-Methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-amine [0326]
N-(4-Methoxypyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0327]
N-(4-Methoxypyrimidin-2-yl)-6-((3-methyloxetan-3-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0328]
6-(Cyclobutylmethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0329]
N-(4-Methoxypyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,-
4-b]thiazolo[4,5-d]azepin-2-amine [0330]
6-Cyclopropyl-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4--
b]thiazolo[4,5-d]azepin-2-amine [0331]
N-(4-Methoxypyrimidin-2-yl)-6-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0332]
N-(4-Methoxypyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0333]
6-((1-(Methoxymethyl)cyclopropyl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0334]
6-((3,3-Difluorocyclobutyl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0335]
6-(3,3-Difluorocyclobutyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0336]
N-(4-Methoxypyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahyd-
ropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0337]
6-(2-Cyclopropoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0338]
6-(2-Ethoxyethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0339]
6-(1-Methoxypropan-2-yl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0340]
N-(5-Fluoropyrimidin-2-yl)-6-((1-(methoxymethyl)cyclopropyl)methyl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0341]
N-(5-Fluoropyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0342]
6-Cyclopropyl-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-2-amine [0343]
6-(2-Ethoxyethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine [0344]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxypropyl)-4,5,6,7-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine [0345]
N-(4-Methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-2-amine [0346]
N-(4-Methylpyrimidin-2-yl)-6-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[3,4-
-b]thiazolo[4,5-d]azepin-2-amine [0347]
6-Cyclopropyl-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b-
]thiazolo[4,5-d]azepin-2-amine [0348]
N-(4-Methylpyrimidin-2-yl)-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0349]
N-(4-Methylpyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0350]
N-(4-Methylpyrimidin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0351]
N.sup.2-(6-(Cyclopropylmethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[-
4,5-d]azepin-2-yl)pyrimidine-2,4-diamine [0352]
N.sup.2-(6-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-2-yl) pyrimidine-2,4-diamine [0353]
4-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)butan-2-one [0354]
6-(2-(Azetidin-1-yl)ethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0355]
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(5-fluoropyrimidin-2--
yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0356]
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0357]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-imidazol-2-yl)methyl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0358]
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0359]
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0360]
6-((3-Fluoropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0361]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0362]
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0363]
N-(5-Fluoropyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0364]
N-(5-Fluoropyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0365]
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0366]
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0367]
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0368]
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(5-fluoropyrimidin-2-yl)--
4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0369]
4-(2-(4-Methylpyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)butan-2-one [0370]
6-(2-(Azetidin-1-yl)ethyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0371]
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(4-methylpyrimidin-2--
yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0372]
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0373]
6-((1-Methyl-1H-imidazol-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0374]
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0375]
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0376]
6-((3-Fluoropyridin-2-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0377]
6-((2-Methylpyridin-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0378]
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0379]
N-(4-Methylpyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0380]
N-(4-Methylpyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0381]
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0382]
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0383]
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,6,7-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0384]
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(4-methylpyrimidin-2-yl)--
4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0385]
4-(2-(4-Methoxypyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,-
5-d]azepin-6(7H)-yl)butan-2-one [0386]
6-(2-(Azetidin-1-yl)ethyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0387]
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(4-methoxypyrimidin-2-
-yl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0388]
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0389]
N-(4-Methoxypyrimidin-2-yl)-6-((1-methyl-1H-imidazol-2-yl)methyl)-4,5,6,7-
-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0390]
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0391]
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5-
,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0392]
6-((3-Fluoropyridin-2-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0393]
N-(4-Methoxypyrimidin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0394]
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7-
-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0395]
N-(4-Methoxypyrimidin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0396]
N-(4-Methoxypyrimidin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0397]
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0398]
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0399]
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-4,5,6,7--
tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0400]
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(4-methoxypyrimidin-2-yl)-
-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0401]
4-(2-(6-Methylpyridin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-d-
]azepin-6(7H)-yl)butan-2-one [0402]
6-(2-(Azetidin-1-yl)ethyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0403]
6-((4-Cyclopropyl-1-methyl-1H-pyrrol-2-yl)methyl)-N-(6-methylpyridin-2-yl-
)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0404]
6-((1-Cyclopropyl-1H-pyrrol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0405]
6-((1-Methyl-1H-imidazol-2-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0406]
6-((1-Cyclopropyl-1H-pyrazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,-
7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0407]
6-((1-Cyclopropyl-1H-pyrazol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,-
7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0408]
6-((3-Fluoropyridin-2-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tetrahy-
dropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0409]
N-(6-Methylpyridin-2-yl)-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7--
tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0410]
6-((2-Cyclopropylpyridin-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0411]
N-(6-Methylpyridin-2-yl)-6-(pyrimidin-4-ylmethyl)-4,5,6,7-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0412]
N-(6-Methylpyridin-2-yl)-6-((2-methylpyrimidin-4-yl)methyl)-4,5,6,7-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0413]
6-((2,5-Dimethylthiazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0414]
6-((2,4-Dimethylthiazol-5-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0415]
6-((2-Cyclopropyloxazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,7-tet-
rahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0416]
6-((2-Cyclopropyl-5-methyloxazol-4-yl)methyl)-N-(6-methylpyridin-2-yl)-4,-
5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0417]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-2-methylpropyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0418]
N-(5-Fluoropyrimidin-2-yl)-6-(1-methoxypropan-2-yl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0419]
N-(5-Fluoropyrimidin-2-yl)-6-4(S)-tetrahydrofuran-2-yl)methyl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0420]
N-(6-Methylpyridin-2-yl)-6-4(S)-tetrahydrofuran-2-yl)methyl)-4,5,6,8-tetr-
ahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0421]
6-((5-Methylisoxazol-3-yl)methyl)-N-(6-methylpyridin-2-yl)-4,5,6,8-tetrah-
ydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0422]
N-(5-Fluoro-4-methylpyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydro-
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0423]
N-(5-Fluoropyrimidin-2-yl)-6-(3-(methylamino)propyl)-4,5,6,8-tetrahydropy-
razolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0424]
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-1
(S)-methyl-ethyl)-4,5,6,8-tetrahydro
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0425]
3-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(8H)-yl)propan-1-ol [0426]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(2-methoxyethoxy)ethyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0427]
6-(2-Ethoxyethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine [0428]
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0429]
N-(5-Fluoropyrimidin-2-yl)-6-(2-morpholinoethyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0430]
6-(2-Fluoroethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3-
,4-b]thiazolo[4,5-d]azepin-2-amine [0431]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0432]
N-(5-Fluoropyrimidin-2-yl)-6-((1-methyl-1H-pyrazol-3-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0433]
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0434]
N-(5-Fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-4,5,6,8-
-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0435]
N-(5-Fluoropyrimidin-2-yl)-6-((tetrahydrofuran-3-yl)methyl)-4,5,6,8-tetra-
hydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0436]
N-(5-Fluoropyrimidin-2-yl)-6-((5-(methoxymethyl)pyridin-2-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0437]
N-(5-Fluoropyrimidin-2-yl)-6-(3-(piperidin-1-yl)propyl)-4,5,6,8-tetrahydr-
opyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0438]
N-(4-Methylpyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0439]
6-((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)-N-(4-methylpyrimidin-2-yl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0440]
N-(5-Fluoropyrimidin-2-yl)-6-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-4-
,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0441]
6-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6-
,8-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0442]
6-(3-Fluoropropyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[-
3,4-b]thiazolo[4,5-d]azepin-2-amine [0443]
N-(5-Fluoropyrimidin-2-yl)-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0444]
4-(3-(2-((5-Fluoropyrimidin-2-yl)amino)-4,5-dihydropyrazolo[3,4-b]thiazol-
o[4,5-d]azepin-6(8H)-yl)propyl)thiomorpholine 1,1-dioxide [0445]
N-(4-Methylpyrimidin-2-yl)-6-(pyrimidin-2-ylmethyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0446]
6-(3-(3,5-Dimethylmorpholino)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine [0447]
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-t-
etrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
trihydrochloride [0448]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methy-
l)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
monohydrochloride and [0449]
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine dihydrochloride
dihydrate.
[0450] Particularly relevant to the present invention is the
tautomeric pair that exists for the pyrazole ring, illustrated
below:
##STR00018##
[0451] In this specification, reference to a generic formula or a
compound as such indicating one tautomer is to be understood to
refer to the tautomeric pair and the other tautomer thereof.
[0452] The disclosed compounds also include all pharmaceutically
acceptable isotopic variations, in which at least one atom is
replaced by an atom having the same atomic number, but an atomic
mass different from the atomic mass usually found in nature.
Examples of isotopes suitable for inclusion in the disclosed
compounds include, without limitation, isotopes of hydrogen, such
as .sup.2H and .sup.3H; isotopes of carbon, such as .sup.13C and
.sup.14C; isotopes of nitrogen, such as .sup.15N; isotopes of
oxygen, such as .sup.17O and .sup.18O; isotopes of phosphorus, such
as .sup.32P and .sup.33P; isotopes of sulfur, such as .sup.35S;
isotopes of fluorine, such as .sup.18F; and isotopes of chlorine,
such as .sup.36Cl. Use of isotopic variations (e.g., deuterium,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements. Additionally, certain
isotopic variations of the disclosed compounds may incorporate a
radioactive isotope (e.g., tritium, .sup.3H, or .sup.14C), which
may be useful in drug and/or substrate tissue distribution studies.
Substitution with positron emitting isotopes, such as .sup.11C,
.sup.18F, .sup.15O and .sup.13N, can be useful in Positron Emission
Topography (PET) studies for examining substrate receptor
occupancy. Isotopically-labelled compounds of Formula (I) to (III)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples using appropriate isotopically-labeled
reagents in place of the non-labeled reagents previously
employed.
DEFINITION OF TERMS
[0453] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0454] For the avoidance of doubt it is to be understood that in
this specification "(C.sub.1-C.sub.6)" means a carbon radical
having 1, 2, 3, 4, 5 or 6 carbon atoms. "(C.sub.0-C.sub.6)" means a
carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. In this
specification "C" means a carbon atom, "N" means a nitrogen atom,
"0" means an oxygen atom and "S" means a sulphur atom.
[0455] In the case where a subscript is the integer 0 (zero) the
radical to which the subscript refers, indicates that the radical
is absent, i.e. there is a direct bond between the radicals.
[0456] In the case where a subscript is the integer 0 (zero) and
the radical to which the subscript refers is alkyl, this indicates
the radical is a hydrogen atom.
[0457] In this specification, unless stated otherwise, the term
"bond" refers to a saturated covalent bond. When two or more bonds
are adjacent to one another, they are assumed to be equal to one
bond. For example, a radical -A-B-, wherein both A and B may be a
bond, the radical is depicting a single bond.
[0458] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl radicals
and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl,
n-hexyl, i-hexyl or t-hexyl. The term "(C.sub.0-C.sub.3)alkyl"
refers to an alkyl radical having 0, 1, 2 or 3 carbon atoms and may
be methyl, ethyl, n-propyl and i-propyl.
[0459] In this specification, unless stated otherwise, the term
"alkylene" includes both straight and branched difunctional
saturated hydrocarbon radicals and may be methylene (--CH.sub.2--),
ethylene (--CH.sub.2--CH.sub.2--), n-propylene
(--CH.sub.2--CH.sub.2--CH.sub.2--), i-propylene
(--CH--(CH.sub.3)--CH.sub.2--), n-butylene
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--), i-butylene
(--CH.sub.2--CH--(CH.sub.3)--CH.sub.2--), t-butylene
(--CH.sub.2--C--(CH.sub.3)--CH.sub.2--), n-pentylene
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--), i-pentylene
(--CH.sub.2--CH(CH.sub.3)--CH.sub.2--CH.sub.2--), neo-pentylene
(--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--), n-hexylene
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) or
i-hexylene
(--CH.sub.2--CH--(CH.sub.3)--CH.sub.2--CH.sub.2--CH.sub.2--).
[0460] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted carbocycle
containing no heteroatoms, including mono-, bi-, and tricyclic
saturated carbocycles, as well as fused ring systems. Such fused
ring systems can include one ring that is partially or fully
unsaturated such as a benzene ring to form fused ring systems such
as benzo-fused carbocycles. Cycloalkyl includes such fused ring
systems as spirofused ring systems. Examples of cycloalkyl include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
decahydronaphthalene, adamantane, indanyl, fluorenyl and
1,2,3,4-tetrahydronaphthalene and the like. The term
"(C.sub.3-C.sub.7)cycloalkyl" may be cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and the like.
[0461] The term "aryl" refers to an optionally substituted
monocyclic or bicyclic hydrocarbon ring system containing at least
one unsaturated aromatic ring. Examples and suitable values of the
term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl,
indyl, indenyl and the like.
[0462] In this specification, unless stated otherwise, the term
"heteroaryl" refers to an optionally substituted monocyclic or
bicyclic unsaturated, aromatic ring system containing at least one
heteroatom selected independently from N, O or S. Examples of
"heteroaryl" may be, but are not limited to thienyl, pyridinyl,
thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl,
triazinyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl,
imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl,
benzoimidazolyl, benzoxazolyl, benzothiazolyl,
tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl,
benzofuryl, benzothiophenyl, thionaphthyl, indolyl, isoindolyl,
pyridonyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl,
phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl,
imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl,
imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl,
cynnolyl, pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridinyl
and purinyl.
[0463] In this specification, unless stated otherwise, the term
"heterocycle" refers to an optionally substituted, monocyclic or
bicyclic saturated, partially saturated or unsaturated ring system
containing at least one heteroatom selected independently from N, O
and S. Examples of such rings may be, but are not limited to,
morpholinyl, piperazinyl, piperidyl and dioxothiomorpholinyl.
[0464] In this specification, unless stated otherwise, the term
"alkylene-aryl", "alkylene-heteroaryl", "alkylene-heterocycle" and
"alkylene-cycloalkyl" refers respectively to a substituent that is
attached via the alkyl radical to an aryl, heteroaryl, heterocycle
or cycloalkyl radical, respectively. The term
"(C.sub.1-C.sub.6)alkylene-aryl" includes
aryl-C.sub.1-C.sub.6-alkyl radicals such as benzyl, 1-phenylethyl,
2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,
1-naphthylmethyl and 2-naphthylmethyl. The term
"(C.sub.1-C.sub.6)alkylene-heteroaryl" includes
heteroaryl-C.sub.1-C.sub.6-alkyl radicals, wherein examples of
heteroaryl are the same as those illustrated in the above
definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl,
3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl,
3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl,
2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridinylmethyl,
3-pyridinylmethyl, 4-pyridinylmethyl, 1-quinolylmethyl or the
like.
[0465] In this specification, unless stated otherwise, a 5- or
6-membered ring containing one or more atoms independently selected
from C, N, O and S, includes aromatic and heteroaromatic rings as
well as carbocyclic and heterocyclic rings which may be saturated
or unsaturated. Examples of such rings may be, but are not limited
to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl,
triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl,
thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl,
cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.
[0466] In this specification, unless stated otherwise, a 3- to
10-membered ring containing one or more atoms independently
selected from C, N, O and S, includes aromatic and heteroaromatic
rings as well as carbocyclic and heterocyclic rings which may be
saturated or unsaturated. Examples of such rings may be, but are
not limited to imidazolidinyl, imidazolinyl, morpholinyl,
piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl,
tetrahydrothiopyranyl, furyl, pyrrolyl, dihydropyrrolyl isoxazolyl,
isothiazolyl, isoindolinonyl, dihydropyrrolo[1,2-b]pyrazolyl,
oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyrrolyl, thiazolyl,
thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl,
cyclobutyl, azetidinyl, oxadiazolyl, thiadiazolyl, tetrazolyl,
cyclopentyl, cyclopentenyl, cyclo hexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl and cyclooctenyl.
[0467] In this specification, unless stated otherwise, the term
"halo" or "halogen" may be fluoro, chloro, bromo or iodo.
[0468] In this specification, unless stated otherwise, the term
"haloalkyl" means an alkyl radical as defined above, substituted
with one or more halo radicals. The term
"(C.sub.1-C.sub.6)haloalkyl" may include, but is not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and
difluoroethyl. The term "0-C.sub.1-C.sub.6-haloalkyl" may include,
but is not limited to, fluoromethoxy, difluoromethoxy,
trifluoromethoxy and fluoroethoxy.
[0469] In this specification, unless stated otherwise, the term
"cyanoalkyl" means an alkyl radical as defined above, substituted
with one or more cyano.
[0470] In this specification, unless stated otherwise, the term
"optionally substituted" refers to radicals further bearing one or
more substituents which may be, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)haloalkyl, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkylene,
--(C.sub.0-C.sub.6)alkylene-(C.sub.3-C.sub.7)spiroalkylene-(C.sub.0-C.sub-
.6)alkylene, hydroxy, (C.sub.1-C.sub.6)alkylene-oxy, mercapto,
aryl, heterocycle, heteroaryl, (C.sub.1-C.sub.6)alkylene-aryl,
(C.sub.1-C.sub.6)alkylene-heterocycle,
(C.sub.1-C.sub.6)alkylene-heteroaryl, halogen, trifluoromethyl,
pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino,
amido, amidinyl, carboxyl, carboxamide,
(C.sub.1-C.sub.6)alkylene-oxycarbonyl, carbamate, sulfonamide,
ester and sulfonyl.
[0471] In this specification, unless stated otherwise, the term
"independently" means that where more than one substituent is
selected from a number of possible substituents, those substituents
may be the same or different.
[0472] In this specification, unless stated otherwise, the term
"solvate" refers to a complex of variable stoichiometry formed by a
solute (e.g. a compound of Formula (I)) and a solvent. The solvent
is a pharmaceutically acceptable solvent as preferably water; such
solvent may not interfere with the biological activity of the
solute.
[0473] In this specification, unless stated otherwise, the term
"salt" refers to a complex of variable stoichiometry formed by an
ionic form of the solute (e.g. a compound of Formula (I)) and its
counter-ion. For example, a reference to carboxylic acid also
includes the anionic (carboxylate) form, a salt or a solvate
thereof, as well as conventional protected forms. Similarly, a
reference to a basic (for example amino) group also includes the
protonated (for example ammonium) form, a salt or solvate of the
basic (for example amino) group, for example, a hydrochloride salt,
as well as conventional protected forms of such group. Similarly, a
reference to a hydroxyl group also includes the anionic form, a
salt or solvate thereof, as well as conventional protected form of
a hydroxyl group. The salt is a pharmaceutically acceptable salt;
such salt may not interfere with the biological activity of the
solute.
[0474] Pharmaceutically acceptable acid addition salts can be
formed with inorganic and organic acids, e.g. acetate, aspartate,
benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate,
bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide,
isethionate, lactate, lactobionate, laurylsulfate, malate, maleate,
malonate, mandelate, mesylate, methylsulfate, naphthoate,
napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate,
palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
phosphate, polygalacturonate, propionate, stearate, succinate,
sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like. Organic acids from which salts
can be derived include, for example, acetic acid, propionic acid,
glycolic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
toluenesulfonic acid, sulfosalicylic acid, and the like.
[0475] Pharmaceutically acceptable base addition salts can be
formed with inorganic and organic bases. Inorganic bases from which
salts can be derived include, for example, ammonium salts and
metals from columns I to XII of the periodic table. In certain
embodiments, the salts are derived from sodium, potassium,
ammonium, calcium, magnesium, iron, silver, zinc, and copper;
particularly suitable salts include ammonium, potassium, sodium,
calcium, and magnesium salts. Organic bases from which salts can be
derived include, for example, primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, cyclic amines, basic ion exchange resins, and
the like. Certain organic amines include isopropylamine,
benzathine, cholinate, diethanolamine, diethylamine, lysine,
meglumine, piperazine, and tromethamine.
[0476] The pharmaceutically acceptable salts of the invention can
be synthesized from a basic or acidic moiety, by conventional
chemical methods. Generally, such salts can be prepared by reacting
free acid forms of these compounds with a stoichiometric amount of
the appropriate base (such as Na, Ca, Mg, or K hydroxide,
carbonate, bicarbonate, and the like), or by reacting free base
forms of these compounds with a stoichiometric amount of the
appropriate acid. Such reactions are typically carried out in water
or in an organic solvent, or in a mixture of the two. Generally,
use of non-aqueous media like diethylether, ethyl acetate, ethanol,
isopropanol, or acetonitrile is desirable, where practicable. Lists
of additional suitable salts can be found, e.g., in "Remington's
Pharmaceutical Sciences", 20.sup.th ed., Mack Publishing company,
Easton, Pa. (1985); and in "Handbook of Pharmaceutical Salts:
Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH,
Weinheim, Germany, (2002).
[0477] When both a basic and an acid group are present in the same
molecule, the compounds of the invention may also form internal
salts, e.g., zwitterionic molecules.
[0478] In this specification, unless stated otherwise, certain
compounds may exist in one or more particular geometric, optical,
enantiomeric, diastereoisomeric, epimeric, stereoisomeric,
tautomeric, conformational, or anomeric forms, including, but not
limited to, cis- and trans-forms; E- and Z-forms; endo- and
exo-forms, R-, S-, and meso-forms; D- and L-forms; d- and -forms;
(+) and (-) forms; keto-, enol-, and enolate-forms; .alpha.- and
.beta.-forms; axial and equatorial forms; and combinations thereof,
collectively referred to as "isomers" or "isomeric forms".
[0479] Note that specifically included in the term "isomer" are
compounds with one or more isotopic substitutions. For example, H
may be in any isotopic form, including, but not limited to,
.sup.1H, .sup.2H (D), and .sup.3H (T); C may be in any isotopic
form, including, but not limited to, .sup.12C, .sup.13C, O may be
in any isotopic form, including, but not limited to, .sup.16O and
.sup.18O; and the like. F may be in any isotopic form, including,
but not limited to, .sup.19F and .sup.18F; and the like.
[0480] In this specification, unless stated otherwise, the term
"positive allosteric modulator of mGluR.sub.4" or "allosteric
modulator of mGluR.sub.4" refers also to a pharmaceutically
acceptable acid or base addition salt thereof, a stereochemically
isomeric form thereof and an N-oxide form thereof.
[0481] As used herein, the term multiple sclerosis (MS) encompasses
the different forms of the disease, including benign, relapsing
remitting, primary progressive, secondary progressive and
progressive relapsing multiple sclerosis.
Pharmaceutical Compositions
[0482] Allosteric modulators of mGluR.sub.4 described herein, and
the pharmaceutically acceptable salts, solvates and hydrates
thereof can be used in pharmaceutical preparations in combination
with a pharmaceutically acceptable carrier or diluent. Suitable
pharmaceutically acceptable carriers include inert solid fillers or
diluents and sterile aqueous or organic solutions. The allosteric
modulators of mGluR.sub.4 will be present in such pharmaceutical
compositions in amounts sufficient to provide the desired dosage
amount in the range described herein. Techniques for formulation
and administration of the compounds of the instant invention can be
found in Remington: the Science and Practice of Pharmacy, 19.sup.th
edition, Mack Publishing Co., Easton, Pa. (1995).
[0483] The amount of allosteric modulators of mGluR.sub.4,
administered to the subject will depend on the type and severity of
the disease or condition and on the characteristics of the subject,
such as general health, age, sex, body weight and tolerance to
drugs. The skilled artisan will be able to determine appropriate
dosages depending on these and other factors. Effective dosages for
commonly used CNS drugs are well known to the skilled person. The
total daily dose usually ranges from about 0.05-2000 mg.
[0484] The present invention relates to pharmaceutical compositions
which provide from about 0.01 to 1000 mg of the active ingredient
per unit dose. The compositions may be administered by any suitable
route. For example, orally in the form of capsules and the like,
parenterally in the form of solutions for injection, topically in
the form of onguents or lotions, ocularly in the form of eye-drops,
rectally in the form of suppositories, intranasally or
transcutaneously in the form of a delivery system like patches.
[0485] For oral administration, the allosteric modulators of
mGluR.sub.4 thereof can be combined with a suitable solid or liquid
carrier or diluent to form capsules, tablets, pills, powders,
syrups, solutions, suspensions and the like.
[0486] The tablets, pills, capsules, and the like contain from
about 0.01 to about 99 weight percent of the active ingredient and
a binder such as gum tragacanth, acacias, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid, a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0487] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0488] For parenteral administration the disclosed allosteric
modulators of mGluR.sub.4 can be combined with sterile aqueous or
organic media to form injectable solutions or suspensions. For
example, solutions in sesame or peanut oil, aqueous propylene
glycol and the like can be used, as well as aqueous solutions of
water-soluble pharmaceutically-acceptable salts of the compounds.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to
prevent the growth of microorganisms.
[0489] In addition, to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered for example, by
subcutaneously implantation or by intramuscular injection. Thus,
for example, as an emulsion in an acceptable oil, or ion exchange
resins, or as sparingly soluble derivatives, for example, as
sparingly soluble salts.
[0490] Preferably disclosed allosteric modulators of mGluR.sub.4 or
pharmaceutical formulations containing these compounds are in unit
dosage form for administration to a mammal. The unit dosage form
can be any unit dosage form known in the art including, for
example, a capsule, an IV bag, a tablet, or a vial. The quantity of
active ingredient in a unit dose of composition is an effective
amount and may be varied according to the particular treatment
involved. It may be appreciated that it may be necessary to make
routine variations to the dosage depending on the age and condition
of the patient. The dosage will also depend on the route of
administration which may be by a variety of routes including oral,
aerosol, rectal, transdermal, subcutaneous, intravenous,
intramuscular, intraperitoneal and intranasal.
[0491] In the case of the treatment of movement disorders such as
Parkinson's disease, the compounds of the invention can be used
alone or in combination with an agent selected from the group
consisting of: a dopamine precursor such as levodopa, melevodopa
and etilevodopa, levodopa with a selective extracerebral
decarboxylase inhibitor, such as carbidopa (SINEMET.TM.),
benserazide (MADOPAR.TM.), a catechol-O-methyl transferase (COMT)
inhibitor such as entacapone and tolcapone, a COMT inhibitor, a
dopamine agonist such as bromocriptine (PARLODEL.TM.), pramipexole,
ropinorole, apomorphine, rotigotine, cabergoline and pergolide,
lisuride or pergolide (CELANCE.TM.), an anticholinergic such as
benztropine, trihexyphenidyl, procyclidine and biperiden, a
cholinergic agonist, an NMDA receptor antagonist such as
amantadine, an MAO-B inhibitor such as selegiline and rasagiline,
an mGluR.sub.5 antagonist or an A.sub.2A antagonist such as
istradefylline and preladenant an alpha-2 adrenergic antagonist
such as atipamezole or fipamezole, a 5-HT.sub.1A agonist such as
piclozotan or a 5-HT.sub.1A/.sub.1B partial agonist such as
eltoprazine. Finally, in the case of the treatment of iatrogenic
movement disorders, the compounds of the invention can be used in
combination with an agent selected from the group of: a
butyrophenone neuroleptic agent, a diphenylbutylpiperidine
neuroleptic agent, a heterocyclic dibenzazepine neuroleptic agent,
an indolone neuroleptic agent, a phenothiazine neuroleptic agent or
a thioxanthene neuroleptic agent
Methods of Synthesis
[0492] The compounds according to the invention, in particular the
compounds according to the Formula (I) to (III), may be prepared by
methods known in the art of organic synthesis as set forth in part
by the following synthesis schemes. In all of the schemes described
below, it is well understood that protecting groups for sensitive
or reactive groups are employed where necessary in accordance with
general principles of chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (Green T. W. and
Wuts P. G. M., (1991) Protecting Groups in Organic Synthesis, John
Wiley & Sons). These groups are removed at a convenient stage
of the compound synthesis using methods that are readily apparent
to those skilled in the art. The selection of process as well as
the reaction conditions and order of their execution shall be
consistent with the preparation of compounds of Formula (I) to
(III).
[0493] The compounds according to the invention may be represented
as a mixture of enantiomers, which may be resolved into the
individual pure R- or S-enantiomers. If for instance, a particular
enantiomer is required, it may be prepared by asymmetric synthesis
or by derivation with a chiral auxiliary, where the resulting
diastereomeric mixture is separated and the auxiliary group cleaved
to provide the pure desired enantiomers. Alternatively, where the
molecule contains a basic functional group such as an amino or an
acidic functional group such as carboxyl, this resolution may be
conveniently performed by fractional crystallization from various
solvents as the salts of an optical active acid or by other methods
known in the literature (e.g. chiral column chromatography).
[0494] Resolution of the final product, an intermediate or a
starting material may be performed by any suitable method known in
the art (Eliel E. L., Wilen S. H. and Mander L. N., (1984)
Stereochemistry of Organic Compounds, Wiley-Interscience).
[0495] Many of the heterocyclic compounds of the invention can be
prepared using synthetic routes well known in the art (Katrizky A.
R. and. Rees C. W., (1984) Comprehensive Heterocyclic Chemistry,
Pergamon Press).
[0496] The product from the reaction can be isolated and purified
by employing standard techniques, such as extraction,
chromatography, crystallization and distillation.
[0497] The compounds of the invention may be prepared by general
route of synthesis as disclosed in the following methods.
[0498] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 1.Pyrazole g1 can be protected by
p-methoxybenzyl, for example, using standard conditions. Then
compound g2 may be hydrolyzed and the resulting carboxylic acid g3
can be transformed into the corresponding Weinreb amide g4.
Functionalized pyrazole g5 can be obtained from deprotonation of
pyrazole g4 using LDA as a base in THF at -78.degree. C. followed
by the addition of 1,2-dibromo-1,1,2,2-tetrachloroethane. The
aminopyrazole g6 may be obtained by methods such as Buchwald
coupling reactions, known in the art of organic synthesis, mediated
by palladium-complex catalysts such as Pd(OAc).sub.2, in the
presence of a base such as Cs.sub.2CO.sub.3, in a solvent such as
dioxane, at an appropriate temperature. g6 can then be reacted with
allylbromide in the presence of anhydride acetic to give the
tertiary amine g7. Vinyl Grignard reagent can be added on the
Weinreb amide g7 to generate the compound g8 which can undergo
metathesis using Grubbs catalysts. The resulting
.alpha.,.beta.-unsaturated ketone g9 can be reduced in the presence
of H.sub.2 and Pd(OH).sub.2 to afford the ketone g10. The
intermediate compound g10 can be functionalized by R.sub.1X (g11)
in the presence of a base such as NaH, KOtBu or NaOtBu and in the
presence of a crown ether, in a solvent such as DMF or THF, to
yield the intermediate compound g12. Subsequently, ketone g12 can
be transformed into bromoketone g13 by using a brominating agent
such as CuBr.sub.2 or pyridinium tribromium, in a solvent such as
MeOH, at an appropriate temperature. Intermediate compound g13 can
then be cyclized into an aminothiazole g14 by reaction with a
suitable substituted thiourea g12, in a solvent such as the mixture
EtOH/Acetone, at an appropriate temperature. Finally, the expected
compound g15 can be obtained via deprotection of g14 in the
presence of TFA or a mixture of TFA/TfOH, at an appropriate
temperature when p-methoxybenzyl is used as the protecting
group.
##STR00019## ##STR00020##
[0499] In general, substituted thiourea M-NH--C(.dbd.S)--NH.sub.2
g12, used in Scheme 1, are prepared according to methods known by
persons skilled in the art. For example, 5-fluoropyrimidin-2-amine
can be reacted with ethyl carbonisothiocyanatidate in acetonitrile,
then the resulting product can be treated with ammonium formate in
ammonia affording the thiourea
5-fluoropyrimidin-2-yl-NHC(.dbd.S)--NH.sub.2.
[0500] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 2. The aminopyrazole g16 may be obtained by
methods such as Buchwald coupling reactions, known in the art of
organic synthesis, mediated by palladium-complex catalysts such as
Pd(OAc).sub.2 or Pd.sub.2(dba).sub.3, in the presence of a base
such as Cs.sub.2CO.sub.3, in a solvent such as dioxane, at an
appropriate temperature. g16 can then be reacted with allylbromide
in the presence of anhydride acetic to give the tertiary amine g17.
Vinyl Grignard reagent can be added on the Weinreb amide g17 to
generate the compound g18 which can undergo metathesis using Grubbs
catalysts. The resulting .alpha.,.beta.-unsaturated ketone g19 can
be reduced in the presence of H.sub.2 or ammonium formate, and
Pd(OH).sub.2 to afford the ketone g11. Intermediate compound g11
can then be cyclized into the aminothiazole g14 by reaction with a
suitable substituted thiourea g12 in the presence of diiodine in a
solvent such as pyridine, at an appropriate temperature. Finally,
the expected compound g15 can be obtained via deprotection of g14
in the presence of TFA or a mixture of TFA/TfOH, at an appropriate
temperature when p-methoxybenzyl is used as the protecting
group.
##STR00021##
[0501] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 3. The ketone g10 can be functionalized by
R.sub.1X in the presence of a base such as NaH, KOtBu or NaOtBu, in
the presence of a crown ether, in a solvent such as DMF or THF, to
yield the intermediate compound g11 which can be cyclized into the
aminothiazole g14 by reaction with a suitable substituted thiourea
g12 in the presence of diiodine, in a solvent such as pyridine, at
an appropriate temperature. Finally, the expected compound g15 can
be obtained via deprotection of g14 in the presence of TFA or a
mixture of TFA/TfOH, at an appropriate temperature when
p-methoxybenzyl is used as the protecting group.
##STR00022##
[0502] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 4. The bromoketone g13 can be cyclized into
the aminothiazole g21 by reaction with thiourea g20, in a solvent
such as the mixture EtOH/Acetone, at an appropriate temperature.
The functionalized aminothiazole g14 can be obtained by methods
such as Buchwald coupling reactions, known in the art of organic
synthesis, mediated by palladium-complex catalysts such as
Pd(OAc).sub.2, in the presence of a base such as Cs.sub.2CO.sub.3,
in a solvent such as dioxane, at an appropriate temperature.
Finally, the expected compound g15 can be obtained using methods
described above.
##STR00023##
[0503] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 5. The expected compound g24 can be obtained
after two sequential deprotections. The intermediate compound g23
can be treated with a solution of HCl in dioxane.
##STR00024##
[0504] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 6. The ether g25 can be demethylated in the
presence of BBr.sub.3 using standard methods well known from
persons skilled in the art to yield the hydroxy compound g26.
##STR00025##
[0505] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 7. The intermediate compound g27 can be
functionalized into the morpholinopyridyl g28 by methods such as
Buchwald coupling reactions, known in the art of organic synthesis,
mediated by palladium-complex catalysts such as Pd(OAc).sub.2 or
Pd.sub.2(dba).sub.3, in the presence of a base such as
Cs.sub.2CO.sub.3, in a solvent such as dioxane, at an appropriate
temperature. Finally, the expected compound g29 can be obtained
using methods described above.
##STR00026##
[0506] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 8. The intermediate g31 can be obtained after
Boc deprotection using standard methods well known from persons
skilled in the art. Subsequently, the piperazine g31 can be
functionalized by methods such as reductive amination, known in the
art of organic synthesis to yield the substituted piperidine g32.
Finally, the expected compound g33 can be obtained using methods
described above.
##STR00027##
[0507] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 9. The intermediate g35 can be obtained after
TMS deprotection of derivative g34 using standard methods well
known from persons skilled in the art. Subsequently, the alcohol
g35 can be brominated in the presence of CBr.sub.4 and PPh.sub.3 to
yield the corresponding bromo derivative g36. The functionalized
piperidine g37 could be obtained by nucleophilic substitution of
g36 using classical conditions known in the art of organic
chemistry. Finally, the expected compound g39 can be obtained in 2
steps from ketone g37 using methods described above.
##STR00028##
[0508] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 10. The acid g41 can be obtained after
saponification of the ester g40 using standard methods well known
from persons skilled in the art. Subsequently, the oxadiazole g42
can be synthesized from the derivative g41 in the presence of
hydroxyacetimidamide and a peptidic coupling agent such as HATU and
a base such as NEt.sub.3 in a solvent such as DMF. Finally, the
expected compound g44 can be obtained in 2 steps from ketone g42
using methods described above.
##STR00029##
[0509] In one embodiment of the present invention, compounds of
Formula (I) may be prepared according to the synthetic sequences
illustrated in Scheme 11. The amino derivative g46 can be obtained
after deprotection of the corresponding N-phthalimide protected
compound g45 using standard methods well known from persons skilled
in the art. Subsequently, the dioxothiomorpholine g48 can be
synthesized from the derivative g46 by cyclization with
vinylsulfonylethene g47 in a solvent such as dioxane. Finally, the
expected compound g50 can be obtained in 2 steps from ketone g48
using methods described above.
##STR00030##
EXPERIMENTAL
[0510] Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without further
purification.
[0511] Specifically, the following abbreviations may be used in the
examples and throughout the specification.
TABLE-US-00001 ACN (Acetonitrile) AcOH (Acetic acid) atm
(Atmosphere) BBr.sub.3 (Boron tribromide) CBr.sub.4 (Carbon
tetrabromide) CHCl.sub.3 (Chloroform) Cs.sub.2CO.sub.3 (Cesium
carbonate) CuBr.sub.2 (Copper (II) bromide) 1,2-DCE
(1,2-Dichloroethane) DCM (Dichloromethane) DMF (Dimethylformamide)
EtOAc (Ethyl acetate) EtOH (Ethanol) Et.sub.3N (Triethylamine) h
(Hour) HATU
(2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate HBr (Hydrobromic acid) HCl (Hydrochloric acid)
I.sub.2 (Diiodine) KOtBu (Potassium tert-butoxide) K.sub.2CO.sub.3
(Potassium carbonate) LDA (Lithium diisopropylamide) M (Molar) MeOH
(Methanol) mg (Milligrams) MgSO.sub.4 (Magnesium sulfate) min
(Minutes) mL (Milliliters) mmol (Millimoles) Mp (Melting point)
NH.sub.4Cl (Ammonium chloride) NaH (Sodium hydride) NaOH (Sodium
hydroxide) NaOtBu (Sodium tert-butoxide) Na.sub.2CO.sub.3 (Sodium
carbonate) Na.sub.2SO.sub.4 (Sodium sulfate) Na.sub.2S.sub.2O.sub.3
(Sodium thiosulfate) Pd(OAc).sub.2 (Palladium(II)acetate)
Pd(OH).sub.2 (Palladium(II) hydroxide) Pd.sub.2(dba).sub.3
(Tris(dibenzylideneacetone)dipalladium(0)) Prep. HPLC (Preparative
high pressure liquid chromatography) Prep. TLC (Preparative thin
layer chromatography) rt (Room temperature) RT (Retention Time) TFA
(Trifluoroacetic acid) THF (Tetrahydrofuran) TLC (Thin layer
chromatography) UPLC-MS (Ultra Performance Liquid Chromatography
Mass Spectrometry) Xantphos
(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)
[0512] All references to brine refer to a saturated aqueous
solution of NaCl. Unless otherwise indicated, all temperatures are
expressed in .degree. C. (degrees Centigrade). All reactions are
conducted under an inert atmosphere at room temperature unless
otherwise noted.
[0513] Most of the reactions were monitored by thin-layer
chromatography on 0.25 mm Merck silica gel plates (60E-254),
visualized with UV light. Flash column chromatography was performed
on prepacked silica gel cartridges (15-40 .mu.M, Merck).
[0514] Melting point determination was performed on a
Electrothermal 1002D apparatus.
[0515] .sup.1H-NMR spectra were recorded on a Bruker 300 MHz
spectrometer and on a Jeol JNM-LA 400 MHz spectrometer. Chemical
shifts are expressed in parts per million (ppm, .delta. units).
Coupling constants are in units of hertz (Hz) Splitting patterns
describe apparent multiplicities and are designated as s (singlet),
d (doublet), t (triplet), q (quadruplet), m (multiplet), br
(broad).
EXAMPLES
Example 1
3-((2-(5-Fluoropyrimidin-2-Ylamino)-4,5-Dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)methyl)benzonitrile (Compound Number 1-1)
Ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
[0516] According to Scheme 1, Step 1: A suspension of ethyl
1H-pyrazole-4-carboxylate (112 g, 799 mmol),
1-(chloromethyl)-4-methoxybenzene (119 mL, 879 mmol) and
K.sub.2CO.sub.3 (166 g, 1.20 mol) in ACN (900 mL) was stirred at
reflux for 4 h. At rt, the mixture was filtered and concentrated
under reduced pressure. The resulting yellow oil was triturated in
petroleum ether and the precipitate was isolated by filtration and
dried under reduced pressure to afford the title compound (208 g,
quantitative) as a white solid.
[0517] UPLC-MS (M1): RT=1.01 min; MS m/z ES.sup.+=261.
1-(4-Methoxybenzyl)-1H-pyrazole-4-carboxylic acid
[0518] According to Scheme 1, Step 2: A solution of NaOH (48.0 g,
1.21 mol) in water (180 mL) was added over a period of 1 h, at
80.degree. C., to a solution of ethyl
1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (208 g, 799 mmol) in
THF/EtOH/H.sub.2O (1:1:0.2, 500 mL). The mixture was stirred at
80.degree. C. for 1 h. The mixture was diluted with cold H.sub.2O
and was washed three times with EtOAc. The aqueous layer was
acidified to pH 2 with HCl 12N. The resulting precipitate was
collected, washed with H.sub.2O and diluted in EtOAc. The organic
layer was dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The product was slurried in petroleum ether and
dried under high vacuum to provide the title compound (93.6 g, 50%)
as a white solid.
[0519] UPLC-MS (M1): RT=0.77 min; MS m/z ES.sup.-=231.
N-Methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide
[0520] According to Scheme 1, Step 3: A solution of
1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (162 g, 698
mmol), oxalyl chloride (77.0 ml, 907 mmol) and DMF (2 mL) in DCM
(811 mL) was stirred at rt for 2 h. After evaporation, the crude
product was dissolved in DCM (322 mL) and the resulting solution
was added at 0.degree. C. over a period of 30 min to a solution of
N,O-dimethylhydroxylamine hydrochloride (102 g, 1.05 mol) in DCM
(811 mL), followed by Et.sub.3N (252 mL, 1.81 mol). The mixture was
stirred at rt for 2 h. The reaction was quenched with a saturated
aqueous solution of Na.sub.2CO.sub.3 (300 mL) and the aqueous layer
was extracted with DCM. The organic layer was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford the title compound (181 g, 94%) as a white solid.
[0521] UPLC-MS (M1): RT=0.73 min; MS m/z ES.sup.+=276.
5-Bromo-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide
[0522] According to Scheme 1, Step 4: In a flask equipped with a
mechanical stirrer, at -78.degree. C. and under N.sub.2 atm, a LDA
solution (327 mL, 654 mmol) was added to a suspension of
N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide
(90.0 g, 327 mmol) in anhydrous THF (1.5 L), over 55 min. The
reaction mixture was stirred at -78.degree. C. for 45 min. Then at
-78.degree. C., 1,2-dibromo-1,1,2,2-tetrachloroethane (117 g, 360
mmol) was added to the reaction mixture over 1 h and the mixture
was allowed to warm to -40.degree. C. over 1 h. At -10.degree. C.,
a saturated solution of NH.sub.4Cl (400 mL) was added over 30 min
to the mixture followed by EtOAc (1 L) and brine (1 L). The aqueous
layer was extracted twice with EtOAc (2 L). The organic layers were
combined, dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The crude residue was diluted with EtOAc and
filtered on a celite pad. The filtrate was concentrated under
reduced pressure to afford the title compound (quantitative).
[0523] UPLC-MS (M1): RT=0.86 min; MS m/z ES.sup.+=354.
5-(Benzylamino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carbo-
xamide
[0524] According to Scheme 1, Step 5:
5-Bromo-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide
(160 g, 452 mmol) was dissolved in dioxane (700 mL), previously
satured with N.sub.2 atm. Then phenylmethanamine (290 g, 2.71 mol),
Cs.sub.2CO.sub.3 (177 g, 542 mmol), Xantphos (15.7 g, 27.1 mmol)
and Pd(OAc).sub.2 (10.1 g, 13.5 mmol) were added to the mixture and
the reaction mixture was stirred at 110.degree. C. for 8 h. The hot
crude solution was filtered on a celite pad and washed with EtOAc
(1 L). The filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography on silca
gel using petroleum ether (100%) to cyclohexane/EtOAc (80/20) as
eluent. The resulting product was diluted in EtOAc (2 L). The
organic layer was washed two times with HCl 1N (1 L), brine (1 L),
was dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to afford the title compound (70 g, 41%).
[0525] UPLC-MS (M1): RT=1.04 min; MS m/z ES.sup.+=381.
5-(Allyl(benzyl)amino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole--
4-carboxamide
[0526] According to Scheme 1, Step 6: To a solution of
5-(benzylamino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carb-
oxamide (66.1 g, 174 mmol) in anhydrous DMF (600 mL) and anhydrous
THF (600 mL) at 0.degree. C., was added portionwise 60% NaH (20.8
g, 521 mmol). The mixture was stirred for 30 min. Then
3-bromoprop-1-ene (44.1 g, 365 mmol) was added to the mixture and
the reaction mixture was stirred for 30 min at rt. After cooling to
0.degree. C., cold water (300 mL) was added slowly to the reaction
mixture. Then the mixture was extracted with EtOAc (2 L). The
organic layers were combined, washed with brine (1 L), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford the title compound (quantitative).
[0527] UPLC-MS (M1): RT=1.18 min; MS m/z ES.sup.+=421.
1-(5-(Allyl(benzyl)amino)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)prop-2-en-1--
one
[0528] According to Scheme 1, Step 7: Under N.sub.2, to a solution
of
5-(allyl(benzyl)amino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-
-4-carboxamide (80.0 g, 190 mmol) in anhydrous THF (1.5 L) was
added dropwise over 40 min, at 0.degree. C., vinylmagnesium bromide
(533 mL, 533 mmol). After stirring the reaction mixture for 1 h,
acetic anhydride (150 mL) was added followed by MeOH (150 mL). Then
25% of the reaction mixture was removed under reduced pressure and
EtOAc (2 L) was added. The mixture was washed with an aqueous
solution of NH.sub.4Cl. The organic layer was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford the title compound (quantitative). The crude was used in the
next step without any further purification.
[0529] UPLC-MS (M1): RT=1.26 min; MS m/z ES.sup.+=388.
(Z)-8-Benzyl-1-(4-methoxybenzyl)-7,8-dihydropyrazolo[3,4-h]azepin-4(1H)-on-
e
[0530] According to Scheme 1, Step 8: Under N.sub.2, to a solution
of
1-(5-(allyl(benzyl)amino)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)prop-2-en-1-
-one crude (90.0 g, 232 mmol) in 1,2-dichloroethane (7.5 L) was
added Grubbs catalyst 1st generation (3.82 g, 4.65 mmol) and the
reaction mixture was stirred at reflux for 1 h. As the reaction was
not complete, 0.01 eq of Grubbs reagent was added each 30 min over
4 h and the reaction mixture was stirred overnight under oxygen.
Then the reaction mixture was poured on a flash column
chromatography with silica gel and the product was purified using
petroleum ether/EtOAc (100:0 to 50:50) as eluent to afford the
title compound (31.7 g, 38%).
[0531] UPLC-MS (M1): RT=1.05 min; MS m/z ES.sup.+=360.
1-(4-Methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
[0532] According to Scheme 1, Step 9: To a solution of
(Z)-8-benzyl-1-(4-methoxybenzyl)-7,8-dihydropyrazolo[3,4-b]azepin-4(1H)-o-
ne (23.3 g, 64.8 mmol) in EtOH (365 mL) was added AcOH (365 mL).
Then under N.sub.2, Pd(OH).sub.2 (15.17 g, 13.0 mmol) was added and
the mixture was stirred under H.sub.2 with a vigourous agitation
for 6 h. The reaction mixture was filtered on a celite pad, the pad
was washed with DCM/EtOH (1:1, 300 mL) and then with EtOH (300 mL).
The filtrate was concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on silica gel
using DCM/MeOH (100:0 to 98.5:1.5) as eluent to afford the title
compound (12.8 g, 73%).
[0533] UPLC-MS (M1): RT=0.66 min; MS m/z ES.sup.+=272; .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta.: 7.55 (1H, s), 7.15-7.05 (3H, m),
6.90 (2H, d), 5.00 (2H, s), 3.70 (3H, s), 3.35 (2H, m), 2.50 (2H,
m), 1.90 (2H, m).
3-((1-(4-Methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8(1H-
)-yl)methyl)benzonitrile
[0534] According to Scheme 1, Step 10: To a solution of
1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
(1.00 g, 3.69 mmol) in THF (20 mL) were added consecutively
18-crown-6 (1.46 g, 5.54 mmol), KOtBu (827 mg, 7.38 mmol) and after
stirring for 5 minutes, 3-(bromomethyl)benzonitrile (1.45 g, 7.38
mmol). The mixture was stirred at reflux overnight. The reaction
was carefully quenched with water and the mixture was diluted with
EtOAc. The separated aqueous layer was extracted with EtOAc. The
organic layers were combined, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography on silica gel using
petroleum ether/EtOAc (90:10 to 30:70) as eluent to afford the
title compound (410 mg, 29%) as a beige solid.
[0535] UPLC-MS (M2): RT=2.91 min; MS m/z ES.sup.+=387.
3-((5-Bromo-1-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]aze-
pin-8(1H)-yl)methyl)benzonitrile
[0536] According to Scheme 1, Step 11: A solution of
3-((1-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8(1-
H)-yl)methyl)benzonitrile (410 mg, 1.06 mmol) and CuBr.sub.2 (356
mg, 1.59 mmol) in MeOH (20 mL) was stirred at reflux for 4 h. After
evaporation of MeOH, the residue was suspended in DCM and an
aqueous solution of Na.sub.2CO.sub.3. The separated aqueous layer
was extracted twice with DCM. The combined organic layers were
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to provide a brown oil. The crude oil was purified by flash column
chromatography on silica gel using petroleum ether/EtOAc (90:10 to
50:50) as eluent to afford the title compound (210 mg, 43%) as a
white viscous solid.
[0537] UPLC-MS (M2): RT=3.07 min; MS m/z ES.sup.+=465.
3-((2-(5-Fluoropyrimidin-2-ylamino)-7-(4-methoxybenzyl)-4,5-dihydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-6(7H)-yl)methyl)benzonitrile
[0538] According to Scheme 1, Step 12: A solution of
3-((5-bromo-1-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]az-
epin-8(1H)-yl)methyl)benzonitrile (210 mg, 0.45 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (78 mg, 0.45 mmol) in EtOH (15
mL) and acetone (15 mL) was stirred at 50.degree. C. overnight. As
the conversion was not complete, 1-(5-fluoropyrimidin-2-yl)thiourea
(78.0 mg, 0.45 mmol) was added and the reaction mixture was stirred
at 60.degree. C. for 3 h, at 70.degree. C. for 4 h, then at
60.degree. C. overnight. After cooling down to rt, the resulting
precipitate was filtered to give the HBr salt of the title compound
(180 mg). The resulting salt was partitioned between aqueous
Na.sub.2CO.sub.3 and DCM and the two phases were separated. The
aqueous layer was extracted twice with DCM and three times with
EtOAc. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to afford the title compound (100 mg, 41%) as a white solid.
[0539] UPLC-MS (M2): RT=3.27 min; MS m/z ES.sup.+=539.
3-((2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5-
-d]azepin-6(7H)-yl)methyl)benzonitrile
[0540] According to Scheme 1, Step 13: A solution of
3-((2-(5-fluoropyrimidin-2-ylamino)-7-(4-methoxybenzyl)-4,5-dihydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-6(7H)-yl)methyl)benzonitrile (100
mg, 0.19 mmol) in TFA (3 mL) was stirred at 60.degree. C. for 2 h.
Excess of TFA was evaporated and the residue was partitioned
between aqueous Na.sub.2CO.sub.3 and DCM. The separated aqueous
layer was extracted twice with DCM. The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude solid was purified by flash
column chromatography on silica gel using DCM/MeOH (100:0 to 97:3)
as eluent to afford the title compound (20 mg, 25%) as a white
solid.
[0541] Mp: 282-284.degree. C.; UPLC-MS (M2): RT=2.93 min; MS m/z
ES.sup.+=419; .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.95
(1H, s), 11.69 (1H, s), 8.72 (2H, d), 7.84 (1H, s), 7.76-7.30 (3H,
m), 7.57 (1H, t), 4.65 (2H, s), 3.05-3.03 (2H, m).
Example 2
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-1(S)-methyl-ethyl)-4,5,6,8-tetrahy-
dropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound Number
1-131)
(S)--N-Methoxy-1-(4-methoxybenzyl)-5-(1-methoxypropan-2-ylamino)-N-methyl--
1H-pyrazole-4-carboxamide
[0542] According to Scheme 2, Step 1:
5-Bromo-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide
(2.50 g, 7.06 mmol) was dissolved in dioxane (25 mL), previously
satured with N.sub.2 atm. Then (S)-1-methoxypropan-2-amine (2.96
mL, 28.2 mmol), Cs.sub.2CO.sub.3 (4.60 g, 14.1 mmol), Xantphos
(0.41 g, 0.70 mmol) and Pd.sub.2(dba).sub.3 (0.32 g, 0.35 mmol)
were added to the mixture and the reaction mixture was stirred at
110.degree. C. overnight. The crude solution was filtered on a
celite pad and washed with EtOAc (30 mL). The filtrate was
concentrated under reduced pressure. The crude residue was purified
by flash column chromatography on silica gel using
cyclohexane/EtOAc (80/20) as eluent to afford the title compound
(1.91 g, 74%) as a yellow oil.
[0543] UPLC-MS (M1): RT=0.91 min; MS m/z ES.sup.+=363.
(S)-5-(Allyl(1-methoxypropan-2-yl)amino)-N-methoxy-1-(4-methoxybenzyl)-N-m-
ethyl-1H-pyrazole-4-carboxamide
[0544] According to Scheme 2, Step 2: To a solution of
(S)--N-methoxy-1-(4-methoxybenzyl)-5-(1-methoxypropan-2-ylamino)-N-methyl-
-1H-pyrazole-4-carboxamide (1.91 g, 5.27 mmol) in anhydrous DMF (20
mL) and anhydrous THF (20 mL) at 0.degree. C., was added
portionwise 60% NaH (0.63 g, 15.8 mmol). The mixture was stirred
for 30 min. Then 3-bromoprop-1-ene (1.27 g, 10.5 mmol) was added to
the mixture and the reaction mixture was stirred for 3.5 h at rt.
After cooling to 0.degree. C., cold water (20 mL) was added slowly
to the reaction mixture. The mixture was then extracted with EtOAc
(50 mL). The organic layers were combined, washed with brine, dried
over MgSO.sub.4, filtered and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on
silica gel using cyclohexane/EtOAc (80/20) as eluent to afford the
title compound (1.47 g, 69%) as yellow oil.
[0545] UPLC-MS (M1): RT=1.07 min; MS m/z ES.sup.+=403.1.
(S)-1-(5-(Allyl(1-methoxypropan-2-yl)amino)-1-(4-methoxybenzyl)-1H-pyrazol-
-4-yl) prop-2-en-1-one
[0546] According to Scheme 2, Step 3: Under N.sub.2, to a solution
of
(S)-5-(allyl(1-methoxypropan-2-yl)amino)-N-methoxy-1-(4-methoxybenzyl)-N--
methyl-1H-pyrazole-4-carboxamide (1.37 g, 3.40 mmol) in anhydrous
THF (25 mL) was added dropwise at 0.degree. C., vinylmagnesium
bromide (17.0 mL, 17.0 mmol). After stirring for 30 min, acetic
anhydride (10 mL) was added followed by MeOH (10 mL). The reaction
mixture was diluted with EtOAc and the organic layer was washed
with aqueous NH.sub.4Cl solution then dried over MgSO.sub.4,
filtered and concentrated under reduced pressure to afford the
title compound (quantitative). The crude was used in the next step
without any further purification.
[0547] UPLC-MS (M1): RT=1.17 min; MS m/z ES.sup.+=370.1.
(S,Z)-1-(4-Methoxybenzyl)-8-(1-methoxypropan-2-yl)-7,8-dihydropyrazolo[3,4-
-b]azepin-4(1H)-one
[0548] According to Scheme 2, Step 4: Under N.sub.2, to a solution
of
(S)-1-(5-(allyl(1-methoxypropan-2-yl)amino)-1-(4-methoxybenzyl)-1H-pyrazo-
l-4-yl)prop-2-en-1-one crude (1.25 g, 3.4 mmol) in
1,2-dichloroethane (170 mL) was added Grubbs catalyst 2.sup.nd
generation (0.14 g, 0.17 mmol). The reaction mixture was stirred at
reflux for 1 h. As the reaction was not complete, 0.01 eq of Grubbs
reagent was added twice in 1 h. Then the reaction mixture was
poured on a flash column chromatography with silica gel and the
product was purified using cyclohexane/EtOAc (100:0 to 60:40) as
eluent to afford the title compound (0.84 g, 72%) as a brown
oil.
[0549] UPLC-MS (M1): RT=0.88 min; MS m/z ES.sup.+=342.0.
(S)-1-(4-Methoxybenzyl)-8-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrazol-
o[3,4-b]azepin-4(1H)-one
[0550] According to Scheme 2, Step 5: Under N.sub.2, to a solution
of
(S,Z)-1-(4-methoxybenzyl)-8-(1-methoxypropan-2-yl)-7,8-dihydropyrazolo[3,-
4-b]azepin-4(1H)-one (0.84 g, 2.46 mmol) in MeOH (15 mL) was added
Pd(OH).sub.2 (0.035 g, 0.25 mmol) followed by ammonium formate
(1.55 g, 24.6 mmol). The mixture was stirred at reflux for 1 h and
then filtered on a celite pad, the pad was washed with DCM/MeOH
(1:1, 30 mL). The reaction mixture was diluted with EtOAc and
washed with saturated aqueous NaHCO.sub.3 solution. The organic
layer was dried over MgSO.sub.4, filtered and concentrated under
reduced pressure to afford the title compound (0.72 g, 85%). The
crude was used in the next step without any further
purification.
[0551] UPLC-MS (M1): RT=0.90 min; MS m/z ES.sup.+=344.3.
N-(5-Fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(2-methoxy-1
(S)-methyl-ethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin--
2-amine
[0552] According to Scheme 2, Step 6: To a solution of
(S)-1-(4-methoxybenzyl)-8-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrazo-
lo[3,4-b]azepin-4(1H)-one (0.31 g, 0.90 mmol) in pyridine (5 mL)
were added consecutively 1-(5-fluoropyrimidin-2-yl)thiourea (0.23
g, 1.35 mmol) and I.sub.2 (0.46 g, 1.80 mmol). The mixture was
stirred at 110.degree. C. for 6 h. The mixture was then diluted
with EtOAc and washed with water. The organic layers were combined,
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The crude residue was purified twice by flash column
chromatography on silica gel using first DCM/MeOH (100:0 to 98:2)
as eluent and then DCM/MeOH (99:1) as eluent to afford the title
compound (90 mg, 20%) as a yellow solid.
[0553] UPLC-MS (M1): RT=1.14 min; MS m/z ES.sup.+=496.2.
N-(5-Fluoropyrimidin-2-yl)-6-(2-methoxy-1
(S)-methyl-ethyl)-4,5,6,8-tetrahydro
pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0554] According to Scheme 2, Step 7: A solution of
N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(2-methoxy-1(S)-methyl-e-
thyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(100 mg, 0.19 mmol) in TFA (1.3 mL) was stirred at 60.degree. C.
for 1 h. The mixture was directly purified on a SCX cartridge to
afford a brown powder (60 mg) which was then purified by flash
column chromatography on silica gel using DCM/MeOH (97:3) as
eluent. The resulting solid was then suspended in MeOH and stirred
at reflux for 1 h. After cooling down the powder was filtered off
and dried to afford the title compound (35 mg, 51%) as a yellow
solid.
[0555] Mp: 249-251.degree. C.; UPLC-MS (M1): RT=0.85 min; MS m/z
ES.sup.+=376.2; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.80
(1H, s), 11.63 (1H, s), 8.69 (2H, s), 7.68 (1H, s), 4.24 (1H, s),
3.53 (1H, dd), 3.38 (1H, dd), 3.25 (5H, m), 2.95 (2H, d), 1.15 (3H,
d).
Example 3
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-te-
trahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
Number 1-135)
8((5-Chloropyridin-2-yl)methyl)-1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyra-
zolo[3,4-b]azepin-4(1H)-one
[0556] According to Scheme 3, Step 1: To a solution of
1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
(0.50 g, 1.84 mmol) in THF (9.2 mL) were added consecutively
15-crown-5 (0.61 g, 2.76 mmol), NaOtBu (0.35 g, 3.69 mmol) and
after stirring for 10 min, 5-chloro-2-(chloromethyl)pyridine (0.33
g, 2.00 mmol). The mixture was stirred at reflux for 4 h. The
reaction was quenched with water and the mixture was diluted with
EtOAc. The separated aqueous layer was extracted with EtOAc. The
organic layers were combined, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography on silica gel using
cyclohexane/EtOAc (100:0 to 30:70) as eluent to afford the title
compound (304 mg, 42%) as a yellow oil.
[0557] UPLC-MS (M1): RT=0.98 min; MS m/z ES.sup.+=397-399.
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybe-
nzyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0558] According to Scheme 3, Step 2: To a solution of
8-((5-chloropyridin-2-yl)methyl)-1-(4-methoxybenzyl)-5,6,7,8-tetrahydropy-
razolo[3,4-b]azepin-4(1H)-one (0.24 g, 0.61 mmol) in pyridine (3
mL) were added consecutively 1-(5-fluoropyrimidin-2-yl)thiourea
(0.10 g, 0.61 mmol) and I.sub.2 (0.16 g, 0.61 mmol). The mixture
was stirred at 80.degree. C. for 3 h. The mixture was then diluted
with EtOAc and washed with saturated Na.sub.2S.sub.2O.sub.3
solution and brine. The organic layer was then dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on
silica gel using DCM/EtOAc (100:0 to 50:50) as eluent to afford the
title compound (98 mg, 29%) as a brown solid.
[0559] UPLC-MS (M1): RT=0.99 min; MS m/z ES.sup.+=397-399.
N-(5-Fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-((5-morpholinopyridin-2-y-
l)methyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0560] According to Scheme 7, Step 1:
6-((5-Chloropyridin-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)-7-(4-methoxyb-
enzyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(98 mg, 0.18 mmol) was dissolved in toluene (1.2 mL), previously
satured with N.sub.2 atm. Then morpholine (31.0 mg, 0.36 mmol),
tBuOK (4.60 g, 14.1 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (8.5 mg,
0.02 mmol) and Pd.sub.2(dba).sub.3 (16.3 mg, 0.02 mmol) were added
to the mixture. The reaction mixture was stirred at 120.degree. C.
for 2 h. As the reaction was not complete, the same amount of
reagents was added and the reaction mixture was stirred at
120.degree. C. for an additional 5 h. The crude solution was
filtered on a celite pad and washed with EtOAc. The filtrate was
washed with saturated Na.sub.2CO.sub.3 solution. The organic layer
was then dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude residue was purified by flash
column chromatography on silica gel using DCM/MeOH/1% Et.sub.3N
(100:0 to 97:3) as eluent to afford the title compound (45 mg, 62%)
as a brown solid.
[0561] UPLC-MS (M1): RT=0.85 min; MS m/z ES.sup.+=600.3
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-te-
trahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0562] According to Scheme 7, Step 2: A solution of
N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-((5-morpholinopyridin-2--
yl)methyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(45 mg, 47 .mu.mol) in TFA (0.72 mL) was stirred at 60.degree. C.
for 1 h. The reaction mixture was diluted with DCM and washed with
saturated Na.sub.2CO.sub.3 solution. The aqueous layer was
extracted with DCM and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on
silica gel using DCM/MeOH/1% Et.sub.3N (100:0 to 97:3). The residue
was then purified on a SCX cartridge to afford the title compound
(14 mg, 63%) as a yellow solid.
[0563] UPLC-MS (M1): RT=0.66 min; MS m/z ES.sup.+=480.2;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.86 (1H, bs), 8.69
(2H, s), 8.22 (1H, d), 7.70 (1H, s), 7.44-7.08 (2H, m), 4.56 (2H,
s), 3.74 (4H, t), 3.13 (4H, t), 3.05-2.89 (2H, m), 2.62 (2H,
d).
[0564] The hydrochloride salt form of Compound 1-135 was prepared
according to the experimental procedure herebelow:
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5,6,8-te-
trahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
trihydrochloride salt (Compound Number 1-135.3HCl)
[0565]
N-(5-Fluoropyrimidin-2-yl)-6-((5-morpholinopyridin-2-yl)methyl)-4,5-
,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (60 mg,
125 .mu.mol) was dissolved into 3 mL of HCl 4N in dioxane. The
resulting solution was heated at 80.degree. C. for 3 h. The solvent
was then removed and the resulting solid was washed with hot
isopropanol. After drying under high vacuum, the title compound as
trihydrochloride salt form was obtained (55 mg; brown light
solid).
[0566] Mp: 240.degree. C.; UPLC-MS (M1): RT=0.67 min; MS m/z
ES.sup.+=480.3; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 8.72
(s, 2H), 8.25 (d, 1H), 8.06 (dd, 1H), 7.81 (s, 1H), 7.74 (s, 1H),
4.81 (s, 2H), 3.80-3.70 (m, 5H), 3.50-3.40 (m, 3H), 3.33 (t, 5H),
3.19-3.05 (m, 2H).
Example 4
N-(5-Fluoropyrimidin-2-yl)-6-(2-morpholinoethyl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,54]azepin-2-amine (Compound Number 1-136)
1-(4-Methoxybenzyl)-8-(2-morpholino
ethyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
[0567] According to Scheme 1, Step 10: To a solution of
1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
(0.32 g, 1.19 mmol) in DMF (6.0 mL) was added 60% NaH (95 mg, 2.38
mmol). After 10 min, 4-(2-chloroethyl)morpholine (0.27 g, 1.78
mmol) was added and the mixture was stirred at rt overnight.
Additional 60% NaH (20 mg) and 4-(2-chloroethyl)morpholine (1 eq)
were added and the reaction mixture was stirred at 90.degree. C.
for 4 h. The reaction was carefully quenched with water and the
mixture was diluted with EtOAc. The organic layer was washed with
water, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography on silica gel using DCM/MeOH/1% Et.sub.3N (100:0 to
97:3) as eluent to afford the title compound (304 mg, 42%) as an
orange oil.
[0568] UPLC-MS (M1): RT=0.47 min; MS m/z ES.sup.+=385.5.
5-Bromo-1-(4-methoxybenzyl)-8-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrazo-
lo[3,4-b]azepin-4 (1H)-one
[0569] According to Scheme 1, Step 11: A solution of
1-(4-methoxybenzyl)-8-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrazolo[3,4--
b]azepin-4(1H)-one (256 mg, 0.57 mmol) and pyridinium tribromide
(199 mg, 0.62 mmol) in CHCl.sub.3 (2.8 mL) was stirred at rt for 2
h. The reaction mixture was diluted with DCM. The organic layer was
washed twice with water, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to afford the title compound
(294 mg, 73%). The crude product was used in the next step without
any further purification.
[0570] UPLC-MS (M2): RT=0.62 min; MS m/z ES.sup.+=463-465.
N-(5-Fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(2-morpholinoethyl)-4,5,6-
,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0571] According to Scheme 1, Step 12: A solution of
5-bromo-1-(4-methoxybenzyl)-8-(2-morpholinoethyl)-5,6,7,8-tetrahydropyraz-
olo[3,4-b]azepin-4(1H)-one (294 mg, 0.54 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (102 mg, 0.59 mmol) in EtOH (2.7
mL) and acetone (2.7 mL) was stirred at 90.degree. C. overnight.
The reaction mixture was condensed under reduced pressure. The
crude was dissolved in EtOAc and washed with aqueous
Na.sub.2CO.sub.3. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography on silica gel using DCM/MeOH/1% Et.sub.3N (100:0 to
97:3) as eluent to afford the title compound (202 mg, 56%) as a
brown solid.
[0572] UPLC-MS (M2): RT=0.70 min; MS m/z ES.sup.+=537.4.
N-(5-Fluoropyrimidin-2-yl)-6-(2-morpholinoethyl)-4,5,6,8-tetrahydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0573] According to Scheme 1, Step 13: To a solution of
N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(2-morpholinoethyl)-4,5,-
6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-c]azepin-2-amine (132 mg,
0.25 mmol) in TFA (1.9 mL) was added triisopropylsilane (195 mg,
1.23 mmol). The reaction mixture was stirred at 60.degree. C. for 1
h. The reaction mixture was concentrated under reduced pressure.
The residue was then purified on a SCX cartridge. The solid was
then slurried in EtOH at reflux for 1 h, filtered and dried under
vacuum to afford the title compound (23 mg, 22%) as an off white
solid
[0574] UPLC-MS (M1): RT=0.57 min; MS m/z ES.sup.+=417.2;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.82 (1H, bs), 11.63
(1H, bs), 8.69 (2H, d), 7.66 (1H, s), 3.60-3.53 (4H, m), 3.50-3.42
(2H, m), 3.42-3.35 (2H, m), 3.02-2.97 (2H, dd), 2.60-2.53 (2H, m),
2.44-2.40 (4H, m).
Example 5
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,6-
,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
Number 1-138)
1-(4-Methoxybenzyl)-8-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5,6,7,8-tetr-
ahydro pyrazolo[3,4-b]azepin-4(1H)-one
[0575] According to Scheme 3, Step 1: Under N.sub.2, to a solution
of
1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(1H)-one
(0.50 g, 1.84 mmol) in THF (15 mL) were added consecutively
15-crown-5 (0.61 g, 2.76 mmol), NaOtBu (0.35 g, 3.69 mmol) and
after stirring for 10 min,
3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (0.37 g, 2.76 mmol). The
mixture was stirred at reflux for 2 h. The reaction was quenched
with water and the mixture was diluted with EtOAc. The separated
aqueous layer was extracted with EtOAc. The organic layers were
combined, dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography on silica gel using yclohexane/EtOAc (100:0 to
30:70) as eluent to afford the title compound (410 mg, 61%).
[0576] UPLC-MS (M1): RT=0.82 min; MS m/z ES.sup.+=368.3.
N-(5-Fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-((5-methyl-1,2,4-oxadiazo-
l-3-yl)methyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-am-
ine
[0577] According to Scheme 3, Step 2: To a solution of
1-(4-methoxybenzyl)-8-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5,6,7,8-tet-
rahydropyrazolo[3,4-b]azepin-4(1H)-one (0.38 g, 1.03 mmol) in
pyridine (8 mL) were added consecutively
1-(5-fluoropyrimidin-2-yl)thiourea (0.27 g, 1.55 mmol) and I.sub.2
(0.53 g, 2.07 mmol). The mixture was stirred at 100.degree. C. for
1 h. One equivalent of both reagents was added and the reaction
mixture was stirred at 100.degree. C. for an additional h. The
mixture was then diluted with EtOAc and washed with water. The
organic layers were combined, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude residue was purified
twice by flash column chromatography on silica gel using first
DCM/MeOH (100:0 to 97:3) as eluent and then DCM/MeOH (99:1) as
eluent to afford the title compound (285 mg, 53%).
[0578] UPLC-MS (M1): RT=1.05 min; MS m/z ES.sup.+=520.2.
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,6-
,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0579] According to Scheme 3, Step 3: A solution of
N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-((5-methyl-1,2,4-oxadiaz-
ol-3-yl)methyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-a-
mine (270 mg, 0.52 mmol) in TFA (1.9 mL) was stirred at 60.degree.
C. for 4 h. The reaction mixture was carefully quenched with water
and diluted with EtOAc. The organic layer was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was then taken up in a DCM:MeOH (1:1) mixture (7 mL) and
the formed precipitate was filtered off, rinsed and dried under to
afford the title compound (77 mg, 37%) as a beige solid
[0580] Mp: 245.degree. C.; UPLC-MS (M1): RT=0.80 min; MS m/z
ES.sup.+=400.2; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.6
(1H, s), 8.70 (2H, s), 7.70 (1H, s), 4.65 (2H, s), 3.55-3.45 (2H,
m), 3.10-3.00 (2H, m), 2.55 (3H, s).
[0581] The hydrochloride salt of Compound 1-138 was prepared
according to the experimental procedure herebelow:
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4,5,6-
,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
Number 1-138.HCl)
[0582]
N-(5-Fluoropyrimidin-2-yl)-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl-
)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(1.00 g, 2.50 mmol) was dissolved into 30 mL of HCl 4N in dioxane.
The resulting solution was heated at 80.degree. C. for 3 h. The
solvent was then removed and the resulting solid was washed with
hot isopropanol. After drying under high vacuum, the title compound
as hydrochloride salt form (1.2 eq HCl) was obtained as a beige
powder (1.00 g).
[0583] Mp:>320.degree. C.; UPLC-MS (M1): RT=0.80 min; MS m/z
ES.sup.+=400.0; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 8.70
(2H, s), 7.75 (1H, s), 4.65 (2H, s), 3.60-3.50 (2H, m), 3.10-3.00
(2H, m), 2.55 (3H, s).
Example 6
N-(5-Fluoro-4-methylpyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound Number
1-129)
8-(4-Methoxybenzyl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]th-
iazolo[4,5-d]azepin-2-amine
[0584] According to Scheme 4, Step 1: A solution of
5-bromo-2-(4-methoxybenzyl)-8-(2-methoxyethyl)-5,6,7,8-tetrahydropyrazolo-
[3,4-b]azepin-4(2H)-one (475 mg, 1.16 mmol, prepared according to
Scheme 1) and thiourea (89.0 mg, 1.16 mmol) in EtOH (2.5 mL) and
acetone (2.5 mL) was stirred at 90.degree. C. for 1.5 h. The
reaction mixture was condensed under reduced pressure. The crude
residue was purified by flash column chromatography on silica gel
using DCM/MeOH (100:0 to 98:2) as eluent to afford the title
compound (305 mg, 68%) as a green solid.
[0585] UPLC-MS (M1): RT=0.67 min; MS m/z ES.sup.+=386.5.
N-(5-Fluoro-4-methylpyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(2-methoxyethyl)-
-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0586] According to Scheme 4, Step 2: A solution of
8-(4-methoxybenzyl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]t-
hiazolo[4,5-d]azepin-2-amine (200 mg, 0.39 mmol),
2-chloro-5-fluoro-4-methylpyrimidine (93.0 mg, 0.63 mmol),
Cs.sub.2CO.sub.3 (339 mg, 1.04 mmol), Xantphos (45 mg, 80 .mu.mol)
and Pd(OAc).sub.2 (12 mg, 50 .mu.mol) in dioxane (1.7 mL) was
stirred at 120.degree. C. for 30 min. The crude solution was cooled
down and diluted with 10 mL of water and 10 mL of EtOAc. The
aqueous layer was extracted twice with EtOAc. The combined organic
layers dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography on silica gel using DCM/MeOH (100:0 to 98:2) as
eluent to afford the title compound (138 mg, 54%) as a beige
solid.
[0587] UPLC-MS (M1): RT=1.16 min; MS m/z ES.sup.+=496.2.
N-(5-Fluoro-4-methylpyrimidin-2-yl)-6-(2-methoxyethyl)-4,5,6,8-tetrahydrop-
yrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0588] According to Scheme 4, Step 3: A solution of
N-(5-fluoro-4-methylpyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(2-methoxyethyl-
)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(138 mg, 0.28 mmol) in DCM (0.5 mL) and TFA (2.2 mL) was stirred at
65.degree. C. for 2 h. After cooling down, the reaction mixture was
concentrated under reduced pressure. The residue was purified on a
SCX cartridge. The resulting solid was then washed with MeOH and
DCM and dried to afford the title compound (30 mg, 28%) as a beige
solid.
[0589] Mp: 261-263.degree. C.; UPLC-MS (M1): RT=0.85 min; MS m/z
ES.sup.+=376.4; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.82
(1H, s), 11.49 (1H, s), 8.52 (1H, d), 7.67 (1H, s), 3.60-3.50 (4H,
m), 3.43-3.35 (2H, m), 3.26 (3H, s), 3.05-2.94 (2H, m), 2.44 (3H,
d).
Example 7
N-(5-Fluoropyrimidin-2-yl)-6-(3-(methylamino)propyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound Number
1-130)
N-(5-Fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(3-(methylamino)propyl)-4-
,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0590] According to Scheme 5, Step 1: A solution of tert-butyl
3-(2-(5-fluoropyrimidin-2-ylamino)-8-(4-methoxybenzyl)-4,5-dihydropyrazol-
o[3,4-b]thiazolo[4,5-d]azepin-6(8H)-yl)propyl(methyl)carbamate (140
mg, 0.17 mmol, prepared according to Scheme 3) in HCl 4N in dioxane
(1.6 mL) and a few drops of MeOH was stirred at rt for 30 min. The
reaction mixture was condensed under reduced pressure. The crude
residue was taken up in DCM and neutralized with Et.sub.3N. The
resulting beige precipitate was filtered off and washed with DCM
and water to afford the title compound (30 mg, 37%) as a beige
solid.
[0591] UPLC-MS (M1): RT=0.72 min; MS m/z ES.sup.+=495.2.
N-(5-Fluoropyrimidin-2-yl)-6-(3-(methylamino)propyl)-4,5,6,8-tetrahydropyr-
azolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0592] According to Scheme 5, Step 2: A solution of
N-(5-fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(3-(methylamino)propyl)--
4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (30
mg, 60 .mu.mol) in TFA (0.6 mL) was stirred at 60.degree. C. for 40
min. After cooling down, the reaction mixture was concentrated
under reduced pressure. The residue was dissolved in MeOH and
neutralized with Et.sub.3N. The crude was then purified by
preparative HPLC in basic mode to afford the title compound (6 mg,
28%) as a light yellow solid.
[0593] UPLC-MS (M1): RT=0.61 min; MS m/z ES.sup.+=375.0;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6+0.1% TFA) .delta.: 8.84 (2H, s),
8.15 (1H, s), 3.61-3.39 (4H, m), 3.22-3.07 (2H, m), 3.04-2.86 (2H,
m), 2.62 (3H, s), 2.07-1.83 (2H, m).
Example 8
3-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-6(8H)-yl)propan-1-ol (Compound Number 1-132)
3-(2-(5-Fluoropyrimidin-2-ylamino)-4,5-dihydropyrazolo[3,4-b]thiazolo[4,5--
d]azepin-6(8H)-yl)propan-1-ol
[0594] According to Scheme 6, step 1: To an ice-cooled solution of
N-(5-fluoropyrimidin-2-yl)-6-(3-methoxypropyl)-4,5,6,8-tetrahydropyrazolo-
[3,4-b]thiazolo[4,5-d]azepin-2-amine (34 mg, 91 .mu.mol, prepared
according to Scheme 3) in DCM (2 mL) was added tribromoborane (0.27
mL, 0.27 mmol). The reaction mixture was stirred at 0.degree. C.
for 10 min and 3 h at rt. The mixture was then filtered off. The
resulting yellow solid was purified by flash column chromatography
on silica gel using DCM/MeOH Et.sub.3N (97:3:0.3) as eluent to
afford the title compound (10 mg, 30%) as a yellow solid.
[0595] UPLC-MS (M1): RT=0.70 min; MS m/z ES.sup.+=362.2;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6+0.1% TFA) .delta.: 11.64 (1H,
brs), 8.69 (2H, s), 7.67 (1H, s), 3.47-3.30 (6H, m), 3.02-2.99 (2H,
m), 1.77-1.72 (2H, m).
Example 9
N-(5-Fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-4,5,6,8--
tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
number 1-141)
N-(5-Fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(2-(piperazin-1-yl)ethyl)-
-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0596] According to Scheme 8, step 1: To a solution of tert-butyl
4-(2-(2-(5-fluoropyrimidin-2-ylamino)-8-(4-methoxybenzyl)-4,5-dihydropyra-
zolo[3,4-b]thiazolo[4,5-d]azepin-6(8H)-yl)ethyl)piperazine-1-carboxylate
(48 mg, 76 .mu.mol, prepared according to Scheme 1) in DCM (0.4 mL)
and MeOH (0.4 mL) was added HCl 4N in dioxane (20 .mu.L). The
resulting solution was stirred at rt for 3 h. The reaction mixture
was condensed under reduced pressure. The crude residue was taken
up in MeOH, neutralized with Et.sub.3N and condensed under reduced
pressure. The resulting beige solid (40 mg) was used as such in the
next step.
[0597] UPLC-MS (M1): RT=0.69 min; MS m/z ES.sup.+=356.0.
N-(5-Fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-8-(4-met-
hoxybenzyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0598] According to Scheme 8, step 2: A solution of
N-(5-fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(2-(piperazin-1-yl)ethyl-
)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(40 mg, 75 .mu.mol) and propan-2-one (2 mL) in DCM (0.7 mL) was
stirred at rt for 15 min. NaBH(OAc).sub.3 (21 mg, 97 .mu.mol) was
then added and the reaction mixture was stirred at rt overnight.
37% conversion was observed by UPLC-MS. Another 2 mL of
propan-2-one and 1.3 eq of NaBH(OAc).sub.3 were added and the
mixture was stirred over the week end at rt. Then the reaction
mixture was quenched with NaOH 1N. The organic layer was dried over
MgSO.sub.4, filtered and condensed under reduced pressure. The
resulting light yellow solid (40 mg, 93%) was used as such in the
next step.
[0599] UPLC-MS (M1): RT=0.79 min; MS m/z ES.sup.+=578.0.
N-(5-Fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-4,5,6,8--
tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0600] According to Scheme 8, step 3: A solution of
N-(5-fluoropyrimidin-2-yl)-6-(2-(4-isopropylpiperazin-1-yl)ethyl)-8-(4-me-
thoxybenzyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amin-
e (40 mg, 69 .mu.mol) and triisopropylsilane (55.0 mg, 346 .mu.mol)
in TFA (0.7 mL) was stirred at 60.degree. C. for 100 min. After
cooling down, the reaction mixture was concentrated under reduced
pressure. The residue was purified on a SCX cartridge; the
resulting solid was then washed with MeOH and Et.sub.2O and dried
to afford the title compound (11 mg, 35%) as a light yellow
solid.
[0601] UPLC-MS (M1): RT=0.59 min; MS m/z ES.sup.+=458.0;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6+10% TFA) .delta.: 8.84 (2H, s),
8.07 (1H, s), 4.15-3.92 (2H, m), 3.87-3.33 (13H, m), 3.24-3.06 (2H,
m), 1.32 (6H, d).
Example 10
6-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,-
8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
number 1-148)
8-(3-Hydroxypropyl)-2-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]a-
zepin-4 (2H)-one
[0602] According to Scheme 9, step 1: To a solution of
2-(4-methoxybenzyl)-8-(3-(trimethylsilyloxy)propyl)-5,6,7,8-tetrahydropyr-
azolo[3,4-b]azepin-4 (2H)-one (0.85 g, 2.12 mmol, prepared
according to Scheme 3, step 1) in dioxane (7.1 mL) was added HCl 4N
in dioxane (0.53 mL, 2.12 mmol). The resulting solution was stirred
at rt for 45 min. The reaction mixture was then concentrated under
reduced pressure to afford the title compound (0.66 g, 95%) as a
red oil used as such in the next step.
[0603] UPLC-MS (M1): RT=0.67 min; MS m/z ES.sup.+=330.2.
8-(3-Bromopropyl)-2-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]aze-
pin-4 (2H)-one
[0604] According to Scheme 9, step 2: To a mixture of
8-(3-hydroxypropyl)-2-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]-
azepin-4(2H)-one (0.60 g, 1.82 mmol) and perbromomethane (1.21 g,
3.64 mmol) in THF (9.1 mL) was added trisphenylphosphine
polymer-bounded (1.21 mL, 3.64 mmol). The resulting mixture was
stirred at rt for 10 min and then filtered to remove the resin. The
filtrate was concentrated under reduced pressure to give a red oil
(0.73 g). Precipitation from cold 2-MeTHF afforded the title
compound (0.71 g, 89% yield) as a white powder.
[0605] UPLC-MS (M1): RT=0.96 min; MS m/z ES.sup.+=392.2-394.2.
8-(3-(4,4-Difluoropiperidin-1-yl)propyl)-2-(4-methoxybenzyl)-5,6,7,8-tetra-
hydro pyrazolo[3,4-b]azepin-4 (2H)-one
[0606] According to Scheme 9, step 3: To a mixture of
4,4-difluoropiperidine hydrochloride (0.14 g, 0.89 mmol) and
N(Et).sub.2iPr (0.37 mL, 2.23 mmol) in 2-MeTHF (1.8 mL) was added
8-(3-bromopropyl)-2-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]az-
epin-4(2H)-one (0.35 g, 0.89 mmol). The resulting mixture was
heated at 80.degree. C. for 1.5 h. The reaction mixture was
condensed under reduced pressure. The dark oily residue was then
taken up in EtOAc and washed twice with a brine solution. Aqueous
layer was extracted again and the combined organic layers were
dried over MgSO.sub.4, filtered and condensed under reduced
pressure. The residue was purified by flash column chromatography
on silica gel using DCM/MeOH (100:0 to 98:2) as eluent to afford
the title compound (85 mg, 22%) as a reddish oil.
[0607] UPLC-MS (M1): RT=0.60 min; MS m/z ES.sup.+=433.4.
6-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-8-(4-m-
ethoxy
benzyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-am-
ine
[0608] According to Scheme 9, step 4: To a solution of
8-(3-(4,4-difluoropiperidin-1-yl)propyl)-2-(4-methoxybenzyl)-5,6,7,8-tetr-
ahydropyrazolo[3,4-b]azepin-4(2H)-one (194 mg, 0.45 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (93.0 mg, 0.54 mmol) in pyridine
(3 mL) was added under inert atmosphere I.sub.2 (137 mg, 0.54
mmol). The resulting mixture was stirred at 80.degree. C. for 3 h.
UPLC-MS monitoring showed a 65% conversion. 0.5 eq of both thiourea
derivative and I.sub.2 was added to the medium and the mixture was
heated another 1 h at 80.degree. C. The reaction mixture was
quenched with a saturated aqueous NaHCO.sub.3 solution (20 mL) and
then extracted several times with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel using DCM/MeOH (100:0 to 97:3) as
eluent to give the title compound as an orange oil (100 mg).
Precipitation from cold EtOH afforded the title compound (95 mg,
36%) as a pale pink powder.
[0609] UPLC-MS (M1): RT=0.80 min; MS m/z ES.sup.+=585.4.
6-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,-
8-tetrahydro pyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0610] According to Scheme 9, step 5: A solution of
6-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-(5-fluoropyrimidin-2-yl)-8-(4--
methoxybenzyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-am-
ine (92.0 mg, 0.16 mmol) and triisopropylsilane (0.1 mL, 0.63 mmol)
in TFA (3.2 mL) was stirred at 65.degree. C. for 1 h. The reaction
mixture was concentrated under reduced pressure. The dark residue
was then taken up in DCM and washed twice with a brine solution.
The aqueous layer was extracted again with EtOAc and the combined
organic extracts were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude was purified by
flash column chromatography on silica gel using DCM/MeOH (100:0 to
95:5 (+1% NEt.sub.3)) as eluent to give a yellow powder (28 mg).
Trituration from warm iPrOH afforded the title compound (21 mg,
28%) as a light yellow powder.
[0611] Mp: 238-240.degree. C.; UPLC-MS (M1): RT=0.67 min; MS m/z
ES.sup.+=465.3; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.80
(1H, d), 11.64 (1H, s), 8.69 (2H, s), 7.65 (1H, s), 3.40-3.25 (4H,
m), 3.14-2.87 (2H, m), 2.65-2.40 (2H, m) 2.39 (4H, d), 1.94 (4H,
dt), 1.77 (2H, t).
Example 11
N-(5-Fluoropyrimidin-2-yl)-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-4,5,6-
,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (Compound
Number 1-150)
2-(2-(4-Methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8
(2H)-yl)acetic acid
[0612] According to Scheme 10, step 1: A solution of methyl
2-(2-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8(2H-
)-yl) acetate (200 mg, 0.58 mmol, prepared according to Scheme 3,
step 1) and LiOH (56.0 mg, 2.33 mmol) in MeOH (1 mL), water (0.1
mL) and THF (1 mL) was stirred at rt for 2 h. The reaction mixture
was concentrated under reduced pressure and the crude was taken up
with EtOAc and acidified with HCl 1N. The organic layer was then
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to afford the title compound as an orange solid (150 mg,
78%) and was used as such in the next step.
[0613] UPLC-MS (M1): RT=0.65 min; MS m/z ES.sup.+=330.
2-(4-Methoxybenzyl)-8-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5,6,7,8-tetr-
ahydro pyrazolo[3,4-b]azepin-4(2H)-one
[0614] According to Scheme 10, step 2: To a solution of
2-(2-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8(2H-
)-yl)acetic acid (450 mg, 1.37 mmol), HATU (623 mg, 1.64 mmol) and
N-hydroxyacetimidamide (202 mg, 2.73 mmol) in DMF (10 mL) was added
NEt.sub.3 (525 .mu.L, 4.10 mmol). The resulting solution was
stirred first 30 min at 60.degree. C., then 2 h at 120.degree. C.
15% conversion was observed. A saturated aqueous Na.sub.2CO.sub.3
solution was added to the reaction mixture and extraction was
performed with EtOAc. The organic layer was dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel using
Cyclohexane/EtOAc (100:0 to 30:70) as eluent to afford the title
compound (70 mg, 14%).
[0615] UPLC-MS (M1): RT=0.81 min; MS m/z ES.sup.+=368.3.
N-(5-Fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-((3-methyl-1,2,4-oxadiazo-
l-5-yl)methyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-am-
ine
[0616] According to Scheme 10, step 3: To a solution of
2-(4-methoxybenzyl)-8-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5,6,7,8-tet-
rahydropyrazolo[3,4-b]azepin-4(2H)-one (70 mg.0, 0.19 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (66.0 mg, 0.38 mmol) in pyridine
(2 mL) was added I.sub.2 (97.0 mg, 0.38 mmol) under an inert
atmosphere. The resulting mixture was stirred at 100.degree. C. for
1 h. UPLC-MS monitoring showed a 50% conversion. 1 eq of both
thiourea derivative and I.sub.2 was added to the medium and the
mixture was heated another 1 h at 100.degree. C. The reaction
mixture was quenched with water and then extracted several times
with EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel using
DCM/MeOH (100:0 to 97:3) as eluent to afford the title compound (55
mg, 56%).
[0617] UPLC-MS (M1): RT=1.02 min; MS m/z ES.sup.+=520.2.
N-(5-Fluoropyrimidin-2-yl)-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-4,5,6-
,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0618] According to Scheme 10, step 4: A solution of
N-(5-fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-((3-methyl-1,2,4-oxadiaz-
ol-5-yl)methyl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-a-
mine (55.0 mg, 0.11 mmol) in TFA (0.7 mL) was stirred at 60.degree.
C. for 2 h. The reaction mixture was diluted with EtOAc and
carefully quenched with water. The organic layer was then dried
over MgSO.sub.4, filtered and concentrated under reduced pressure.
The crude was purified by flash column chromatography on silica gel
using DCM/MeOH (100:0 to 94:6) as eluent to afford the title
compound as a grey powder (18 mg, 43%).
[0619] UPLC-MS (M1): RT=0.81 min; MS m/z ES.sup.+=400.1;
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.91 (1H, s), 11.67
(1H, s), 8.70 (2H, s), 7.69 (1H, s), 4.83 (2H, s), 3.65-3.45 (2H,
m), 3.15-3.00 (2H, m), 2.30 (3H, s).
Example 12
4-(3-(2-((5-Fluoropyrimidin-2-yl)amino)-4,5-dihydropyrazolo[3,4-b]thiazolo-
[4,5-d]azepin-6(8H)-yl)propyl)thiomorpholine 1,1-dioxide (Compound
number 1-151)
8-(3-Aminopropyl)-1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]aze-
pin-4(1H)-one
[0620] According to Scheme 11, step 1: To a mixture of
2-(3-(1-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]azepin-8-
(1H)-yl)propyl)iso indo line-1,3-dione (635 mg, 1.38 mmol) in EtOH
(4.6 mL) was added hydrazine (67 .mu.L, 1.38 mmol) and the
resulting mixture was heated at 65.degree. C. for 1 h. An LC-MS
monitoring of the reaction showed a full conversion of the SM with
an extra addition of hydrazine on the carbonyl group. The crude
mixture was poured onto water. Aqueous layer was acidified to pH=2
by the addition of a 6N HCl aq. solution and then heated up to
65.degree. C. for 2-3 min leading to the cleavage of the imino
adduct. The aqueous layer was then neutralized to pH=6-7 by the
addition of a 30% aq. NaOH solution and extracted several times
with EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated under reduced pressure to afford the
title compound (0.36 g, 80%) as a colorless oil.
[0621] UPLC-MS (M1): RT=0.50 min; MS m/z ES.sup.+=329.3.
1-(4-Methoxybenzyl)-8-(3-dioxothiomorpholinopropyl)-5,6,7,8-tetrahydropyra-
zolo[3,4-b]azepin-4(1H)-one
[0622] According to Scheme 11, step 2: A solution of
vinylsulfonylethene (0.11 mL, 1.10 mmol) and
8-(3-aminopropyl)-1-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]az-
epin-4(1H)-one (0.36 g, 1.10 mmol) in dry dioxane (3.7 mL) was
heated at 110.degree. C. for 1.5 h. The reaction mixture was poured
onto water and extracted three times with DCM. The combined organic
layers were dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The crude was purified by flash column
chromatography on silica gel using DCM/MeOH (100:0 to 95:5) as
eluent to afford the title compound (0.34 g, 68%) as a light yellow
oil.
[0623] UPLC-MS (M1): RT=0.65 min; MS m/z ES.sup.+=447.5.
N-(5-Fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(3-dioxothiomorpholinopro-
pyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0624] According to Scheme 11, step 3: To a solution of
1-(4-methoxybenzyl)-8-(3-dioxothiomorpholinopropyl)-5,6,7,8-tetrahydropyr-
azolo[3,4-b]azepin-4(1H)-one (0.34 g, 0.76 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (156 mg, 0.91 mmol) in pyridine
(5.1 mL) was added I.sub.2 (0.23 g, 0.91 mmol). The resulting
solution was heated at 80.degree. C. for 1 h. UPLC-MS monitoring
showed a 80% conversion rate. Then 0.5 eq of both I.sub.2 and
thiourea derivative was added and the mixture was stirred overnight
at 80.degree. C. The crude mixture was then poured onto a brine
solution and extracted several times with EtOAc. The combined
organic layers were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude mixture was purified
by flash column chromatography on silica gel using DCM/MeOH (100:0
to 98:2) as eluent. Trituration in isopropanol afforded the title
compound (167 mg, 37%) as a light yellow powder.
[0625] UPLC-MS (M1): RT=0.87 min; MS m/z ES.sup.+=599.3.
4-(3-(2-((5-Fluoropyrimidin-2-yl)amino)-4,5-dihydropyrazolo[3,4-b]thiazolo-
[4,5-d]azepin-6(8H)-yl)propyl)thiomorpholine 1,1-dioxide
[0626] According to Scheme 11, step 4: A solution of
N-(5-fluoropyrimidin-2-yl)-7-(4-methoxybenzyl)-6-(3-dioxothiomorpholinopr-
opyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
(165 mg, 0.28 mmol) in TFA (5.5 mL) was heated at 65.degree. C. for
1 h. The reaction mixture was concentrated to dryness. The dark
residue was taken up in DCM and neutralized with a saturated
NaHCO.sub.3 aqueous solution and washed twice with a brine
solution. Aqueous layer was extracted again with EtOAc and the
combined organic extracts were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude was purified by
flash column chromatography on silica gel using DCM/MeOH (100:0 to
95:5 (+1% NEt.sub.3) as eluent. Trituration in warm isopropanol
afforded the title compound as a light yellow powder. The target
compound was then solubilized in a mixture of hot DMSO (0.5 mL) and
water (50 .mu.L). The aliquot was then lyophilized for 2 days to
afford the title compound (27 mg, 20% yield) as a beige powder.
[0627] Mp: 272-273.degree. C.; UPLC-MS (M1): RT=0.63 min; MS m/z
ES.sup.+=479.2; .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 11.81
(1H, s), 11.62 (1H, s), 8.69 (2H, s), 7.87-7.44 (1H, m), 3.46-3.33
(4H, m), 3.08 (4H, t), 3.01 (2H, t), 2.87 (4H, t), 1.77 (2H, dd)
+2H under water peak.
Example 13
2-(4-Methoxybenzyl)-8-(3-morpholinopropyl)-5,6,7,8-tetrahydro
pyrazolo[3,4-b]azepin-4(2H)-one (Compound Number 1-140)
2-(4-Methoxybenzyl)-8-(3-morpholinopropyl)-5,6,7,8-tetrahydropyrazolo[3,4--
b]azepin-4(2H)-one
[0628] According to Scheme 3, step 1: To a mixture of
2-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrazolo[3,4-b]azepin-4(2H)-one
(12.0 g, 44.2 mmol) in dry THF (177 mL) were added under an inert
atmosphere 1,4,7,10,13-pentaoxacyclopentadecane (13.1 mL, 66.3
mmol), sodium 2-methylpropan-2-olate (6.38 g, 66.3 mmol) and then 5
min later 4-(3-chloropropyl)morpholine (8.69 g, 53.1 mmol). The
resulting reaction mixture was heated overnight at reflux. An LC-MS
monitoring the reaction showed a 50% conversion rate of the
starting material with no longer evolution. The crude reaction
mixture was then quenched, adding 10 mL of water and the organic
volatiles were removed under vacuo. The brown oily residue was then
taken up in EtOAc and washed twice with a saturated NH.sub.4Cl
solution. The aqueous layer was extracted again several times with
EtOAc and combined organic extracts were dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel using
EtOAc/iPrOH (100:0 to 80:20) as eluent to give the title compound
and 4 g of the starting material (azepine derivative). The reaction
was repeated twice using the recovered starting material and
following the same reaction procedure. Mixed batches (yellow oil)
were then triturated with a mixture Et.sub.2O/Petroleum Ether 2:1
until precipitation. A light yellow powder was filtered off,
slurred twice with Et.sub.2O and dried under high vacuum pressure
to afford the title compound (15 g, 90%) as an off-white
powder.
[0629] UPLC-MS (M1): RT=4.18 min; MS m/z ES.sup.+=399.4.
N-(5-Fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(3-morpholinopropyl)-4,5,-
6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0630] According to Scheme 3, step 2: To a mixture of
2-(4-methoxybenzyl)-8-(3-morpholinopropyl)-5,6,7,8-tetrahydropyrazolo[3,4-
-b]azepin-4 (2H)-one (4.00 g, 10.0 mmol) and
1-(5-fluoropyrimidin-2-yl)thiourea (2.38 g, 13.8 mmol) in pyridine
(67 mL) was added I.sub.2 (3.06 g, 12.05 mmol) under an inert
atmosphere and the resulting mixture was left under stirring for
0.5 h at 80.degree. C. The reaction mixture turned into a dark
solution. An UPLC-MS monitoring of the reaction showed a 65%
conversion rate of the starting material. 0.5 eq of both
1-(5-fluoropyrimidin-2-yl)thiourea and I.sub.2 were added and the
resulting mixture was heated to 80.degree. C. for another 0.5 h.
The crude mixture was diluted with EtOAc and washed with a
saturated NaHCO.sub.3 aqueous solution. The aqueous layer was
extracted again three times with EtOAc. The combined organic layers
were dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel using DCM/MeOH (100:0 to 95:5 (+1%
NEt.sub.3) as eluent. The recovered light yellow powder was then
slurred twice in cold iPrOH, rinsed with Et.sub.2O and dried under
vacuum pressure to afford the title compound (1.4 g, 25%) as a
light yellow powder.
[0631] UPLC-MS (M1); RT=0.80 min; MS m/z ES.sup.+=551.5.
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine
[0632] According to Scheme 3, step 3: a mixture of
N-(5-fluoropyrimidin-2-yl)-8-(4-methoxybenzyl)-6-(3-morpholinopropyl)-4,5-
,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine (240
mg, 436 .mu.mol) and triisopropylsilane (1.21 mL, 5.90 mmol) in TFA
(3.9 mL) was heated at 65.degree. C. for 3 h. The crude mixture was
concentrated to dryness and the residue was taken up in 10 mL of
EtOAc. The resulting organic mixture was quenched with water and
neutralized with 10 mL of a saturated NaHCO.sub.3 aqueous solution.
The aqueous layer was then extracted several times with EtOAc. The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel using DCM/MeOH (100:0
to 95:5 (+1% NEt.sub.3) as eluent. Recrystallization in DMF
(110-120.degree. C.) afforded the title compound (235 mg, 57%) as a
light yellow powder.
[0633] Mp: 251-254.degree. C.; UPLC-MS (M1); RT=4.27 min; MS m/z
ES.sup.+=431.3; .sup.1H-NMR (300 MHz; DMSO-d.sub.6) .delta.: 11.82
(1H, s), 11.64 (1H, s), 8.69 (2H, d), 7.66 (1H, s), 3.58 (4H,$),
3.30 (2H, s), 3.01 (2H, t), 2.33 (6H, d), 1.79 (2H, d), 1.17 (1H,
t).
[0634] The hydrochloride salt of Compound 1-140 was prepared
according to the experimental procedure herebelow:
N-(5-Fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyrazo-
lo[3,4-b]thiazolo[4,5-d]azepin-2-amine dihydrochloride dihydrate
(Compound 1-140.2HCl.2H.sub.2O)
[0635] A mixture of
N-(5-fluoropyrimidin-2-yl)-6-(3-morpholinopropyl)-4,5,6,8-tetrahydropyraz-
olo[3,4-b]thiazolo[4,5-d]azepin-2-amine (0.70 g, 1.63 mmol) and a
4N HCl solution in dioxane (5 mL, 1.63 mmol) was refluxed for 0.5
h. The precipitate was filtered off and rinsed with Et.sub.2O.
After a trituration from boiling iPrOH (85.degree. C., 30 min), the
solid was recovered, rinsed with Et.sub.2O and dried under high
vacuum pressure to afford the title compound (58%) as a light grey
powder.
[0636] Mp: 257-259.degree. C.; UPLC-MS (M1); RT=0.6 min; MS m/z
ES.sup.+=431.3; .sup.1H-NMR (300 MHz; DMSO-d.sub.6) .delta.: 10.71
(1H, s), 8.71 (2H, d), 7.79 (1H, s), 3.94 (2H, s), 3.86-3.65 (2H,
m), 3.56-3.27 (4H, m), 3.27-2.90 (4H, m), 2.07 (2H, d).
[0637] The compounds in the following Table have been synthezised
according to the same methods as previous Examples 1 to 13, as
denoted in the column denoted as "Exp. nr". The compounds denoted
with the asterisk have been exemplified in the Examples.
TABLE-US-00002 TABLE 1 Compounds prepared according to the
Examples. ##STR00031## Co.nr. Exp nr. M R.sup.1 1-1 1* ##STR00032##
##STR00033## 1-2 1 ##STR00034## ##STR00035## 1-3 1 ##STR00036##
##STR00037## 1-4 1 ##STR00038## ##STR00039## 1-5 1 ##STR00040##
##STR00041## 1-6 1 ##STR00042## ##STR00043## 1-7 1 ##STR00044##
##STR00045## 1-8 1 ##STR00046## ##STR00047## 1-9 1 ##STR00048##
##STR00049## 1-10 1 ##STR00050## ##STR00051## 1-11 1 ##STR00052##
##STR00053## 1-12 1 ##STR00054## ##STR00055## 1-13 1 ##STR00056##
##STR00057## 1-14 3 ##STR00058## ##STR00059## 1-15 -- ##STR00060##
##STR00061## 1-16 -- ##STR00062## ##STR00063## 1-17 -- ##STR00064##
##STR00065## 1-18 -- ##STR00066## ##STR00067## 1-19 -- ##STR00068##
##STR00069## 1-20 -- ##STR00070## ##STR00071## 1-21 -- ##STR00072##
##STR00073## 1-22 -- ##STR00074## ##STR00075## 1-23 -- ##STR00076##
##STR00077## 1-24 -- ##STR00078## ##STR00079## 1-25 -- ##STR00080##
##STR00081## 1-26 -- ##STR00082## ##STR00083## 1-27 -- ##STR00084##
##STR00085## 1-28 -- ##STR00086## ##STR00087## 1-29 -- ##STR00088##
##STR00089## 1-30 -- ##STR00090## ##STR00091## 1-31 -- ##STR00092##
##STR00093## 1-32 -- ##STR00094## ##STR00095## 1-33 -- ##STR00096##
##STR00097## 1-34 -- ##STR00098## ##STR00099## 1-35 -- ##STR00100##
##STR00101## 1-36 -- ##STR00102## ##STR00103## 1-37 -- ##STR00104##
##STR00105## 1-38 -- ##STR00106## ##STR00107## 1-39 -- ##STR00108##
##STR00109## 1-40 -- ##STR00110## ##STR00111## 1-41 -- ##STR00112##
##STR00113## 1-42 -- ##STR00114## ##STR00115## 1-43 -- ##STR00116##
##STR00117## 1-44 -- ##STR00118## ##STR00119## 1-45 -- ##STR00120##
##STR00121## 1-46 -- ##STR00122## ##STR00123## 1-48 -- ##STR00124##
##STR00125## 1-49 -- ##STR00126## ##STR00127## 1-50 -- ##STR00128##
##STR00129## 1-51 -- ##STR00130## ##STR00131## 1-52 1 ##STR00132##
##STR00133## 1-53 -- ##STR00134## ##STR00135## 1-54 -- ##STR00136##
##STR00137## 1-55 -- ##STR00138## ##STR00139## 1-56 -- ##STR00140##
##STR00141## 1-57 -- ##STR00142## ##STR00143## 1-58 -- ##STR00144##
##STR00145## 1-59 -- ##STR00146## ##STR00147## 1-60 -- ##STR00148##
##STR00149## 1-61 -- ##STR00150## ##STR00151## 1-62 -- ##STR00152##
##STR00153## 1-63 -- ##STR00154## ##STR00155## 1-64 -- ##STR00156##
##STR00157## 1-65 -- ##STR00158## ##STR00159## 1-66 -- ##STR00160##
##STR00161## 1-67 -- ##STR00162## ##STR00163## 1-68 -- ##STR00164##
##STR00165## 1-69 -- ##STR00166## ##STR00167## 1-70 -- ##STR00168##
##STR00169## 1-71 -- ##STR00170## ##STR00171## 1-72 -- ##STR00172##
##STR00173## 1-73 -- ##STR00174## ##STR00175## 1-74 -- ##STR00176##
##STR00177## 1-75 -- ##STR00178## ##STR00179## 1-76 -- ##STR00180##
##STR00181## 1-77 -- ##STR00182## ##STR00183## 1-78 -- ##STR00184##
##STR00185## 1-79 -- ##STR00186## ##STR00187## 1-80 -- ##STR00188##
##STR00189## 1-81 -- ##STR00190## ##STR00191## 1-82 -- ##STR00192##
##STR00193## 1-83 -- ##STR00194## ##STR00195## 1-84 -- ##STR00196##
##STR00197## 1-85 -- ##STR00198## ##STR00199## 1-86 -- ##STR00200##
##STR00201## 1-87 -- ##STR00202## ##STR00203## 1-88 -- ##STR00204##
##STR00205## 1-89 -- ##STR00206## ##STR00207## 1-90 -- ##STR00208##
##STR00209## 1-91 -- ##STR00210## ##STR00211## 1-92 -- ##STR00212##
##STR00213## 1-93 -- ##STR00214## ##STR00215## 1-94 -- ##STR00216##
##STR00217## 1-95 -- ##STR00218## ##STR00219## 1-96 -- ##STR00220##
##STR00221## 1-97 -- ##STR00222## ##STR00223## 1-98 -- ##STR00224##
##STR00225## 1-99 -- ##STR00226## ##STR00227## 1-100 --
##STR00228## ##STR00229## 1-101 -- ##STR00230## ##STR00231## 1-102
-- ##STR00232## ##STR00233## 1-103 -- ##STR00234## ##STR00235##
1-104 -- ##STR00236## ##STR00237## 1-105 -- ##STR00238##
##STR00239## 1-106 -- ##STR00240## ##STR00241## 1-107 --
##STR00242## ##STR00243## 1-108 -- ##STR00244## ##STR00245## 1-109
-- ##STR00246## ##STR00247## 1-110 -- ##STR00248## ##STR00249##
1-111 -- ##STR00250## ##STR00251## 1-112 -- ##STR00252##
##STR00253## 1-113 -- ##STR00254## ##STR00255## 1-114 --
##STR00256## ##STR00257## 1-115 -- ##STR00258## ##STR00259## 1-116
-- ##STR00260## ##STR00261## 1-117 -- ##STR00262## ##STR00263##
1-118 -- ##STR00264## ##STR00265## 1-119 -- ##STR00266##
##STR00267## 1-120 -- ##STR00268## ##STR00269## 1-121 --
##STR00270## ##STR00271## 1-122 -- ##STR00272## ##STR00273##
1-123 -- ##STR00274## ##STR00275## 1-124 2 ##STR00276##
##STR00277## 1-125 2 ##STR00278## ##STR00279## 1-126 2 ##STR00280##
##STR00281## 1-127 2 ##STR00282## ##STR00283## 1-128 3 ##STR00284##
##STR00285## 1-129 1 ##STR00286## ##STR00287## 1-130 3 ##STR00288##
##STR00289## 1-131 2* ##STR00290## ##STR00291## 1-132 3
##STR00292## ##STR00293## 1-133 3 ##STR00294## ##STR00295## 1-134 3
##STR00296## ##STR00297## 1-135 3* ##STR00298## ##STR00299## 1-136
4* ##STR00300## ##STR00301## 1-137 3 ##STR00302## ##STR00303##
1-138 5* ##STR00304## ##STR00305## 1-139 3 ##STR00306##
##STR00307## 1-140 3* ##STR00308## ##STR00309## 1-141 1
##STR00310## ##STR00311## 1-142 2 ##STR00312## ##STR00313## 1-143 3
##STR00314## ##STR00315## 1-144 3 ##STR00316## ##STR00317## 1-145 1
##STR00318## ##STR00319## 1-146 1 ##STR00320## ##STR00321## 1-147 3
##STR00322## ##STR00323## 1-148 10* ##STR00324## ##STR00325## 1-149
3 ##STR00326## ##STR00327## 1-150 11* ##STR00328## ##STR00329##
1-151 12* ##STR00330## ##STR00331## 1-152 1 ##STR00332##
##STR00333## 1-153 3 ##STR00334## ##STR00335##
UPLC-MS Method 1 (M1):
[0638] UPLC-MS were recorded on Waters ACQUITY UPLC with the
following conditions: Reversed phase HPLC was carried out on
BEH-C.sub.18 cartridge (1.7 .mu.m, 2.1.times.50 mm) from Waters,
with a flow rate of 0.8 mL/min. The gradient conditions used are:
90% A (water+0.1% of formic acid), 10% B (ACN+0.1% of formic acid)
to 100% B at 1.3 minutes, kept till 1.6 minutes and equilibrated to
initial conditions at 1.7 minutes until 2.0 minutes. Injection
volume 5 .mu.L. ES MS detector was used, acquiring both in positive
and negative ionization modes.
UPLC-MS Method 2 (M2):
[0639] UPLC-MS were recorded on Perkin Elmer Series 200 autosampler
and pump, Perkin Elmer PE785A UV detector, API150EX spectrometer
(ES+/-). Agilent Poroshell 120 SB-C.sub.18 column (4.6 mm.times.30
mm, 2.7 micron). [0640] Run Conditions: Injection Volume 10 pi
[0641] HPLC grade water (containing 0.1% formic acid) [0642] HPLC
grade ACN(containing 0.1% formic acid)
TABLE-US-00003 [0642] Total Time Flow Rate % % (min) (ml/min)
Aqueous ACN 1.0 1.8 95 5 2.0 1.8 0 100 4.0 1.8 0 100 5.5 1.8 95
5
[0643] All mass spectra were taken under electrospray ionisation
(ESI) methods.
LC-MS Method 3 (M3):
[0644] UPLC-MS were recorded on Column 1-EXTEND Zorbax SB-C.sub.18,
1.8 .mu.m, 4.6.times.30 mm Column and LC-MS analysis were recorded
on a Waters Micromass ZQ 2996 system with the following conditions:
reversed phase HPLC was carried out on an Zorbax SB-C.sub.18
cartridge (1.8 .mu.m, 4.6.times.30 mm) from Agilent, with a flow
rate of 1.5 mL/min. The gradient conditions used are: 90% A
(water+0.05% of formic acid), 10% B (ACN+0.05% of formic acid) to
100% B at 3.5 min, kept till 3.7 min and equilibrated to initial
conditions at 3.8 min until 4.5 min. Injection volume 5-20 .mu.L.
ES MS detector was used, acquiring both in positive and negative
ionization modes. Cone voltage was 30 V for both positive and
negative ionization modes.
TABLE-US-00004 TABLE 2 Physico-chemical data for some compounds (nd
= not determined). Co. Mp RT (min) Nr (.degree. C.) [MH.sup.+]
Method .sup.1H-NMR data 1-1* 282-284 419.0 2.93 M2 (400 MHz,
DMSO-d.sub.6) .delta.: 11.95 (1H, s), 11.69 (1H, s), 8.72 (2H, d),
7.84 (1H, s), 7.76- 7.30 (3H, m), 7.57 (1H, t), 4.65 (2H, s), 3.05-
3.03 (2H, m) 1-2 265-270 411.9 3.05 M2 (400 MHz, DMSO-d.sub.6)
.delta.: 11.86 (1H, s), 11.61 (1H, s), 8.64 (2H, d), 7.67 (1H, s),
7.34- 7.29 (1H, m), 7.17-7.11 (2H, m), 7.03-6.99 (1H, m), 4.54 (2H,
s), 2.95-2.90 (2H, m) 1-3 nd 360.4 2.81 M2 (400 MHz, DMSO-d.sub.6)
.delta.: 7.61 (1H, s), 3.35 (2H, m), 3.15 (2H, d), 2.94 (2H, m)
2.67 (3H, s), 1.07 (1H, m), 0.38 (2H, m), 0.16 (2H, m) 1-4 nd 425.0
2.91 M2 (400 MHz, DMSO-d.sub.6) .delta.: 8.70-8.53 (2H, br m), 7.65
(1H, s), 6.05 (1H, s), 4.45 (2H, s), 3.21 (2H, m), 2.92 (2H, m),
2.03 (1H, m), 0.95 (2H, m), 0.78 (2H, m) 1-7 266-268 425.1 2.91 M2
(400 MHz, DMSO-d.sub.6) .delta.: 11.87-11.62 (1 H, brs), 8.61 (2H,
s), 7.63 (1H, s), 6.01 (1H, s), 4.55 (2H, s), 3.30 (2H, m), 2.96
(2H, m), 1.88 (1H, m), 0.89 (2H, m), 0.65 (2H, m) 1-8 240-245 441.1
2.95 M2 (400 MHz, CD.sub.3OD) .delta.: 8.22 (2H, s), 7.60 (1H, s),
6.75 (1H, s), 4.40 (2H, s), 3.23-3.17 (2H, m), 2.85-2.79 (2H, m),
2.12-2.05 (1H, m), 0.95-0.90 (2H, m), 0.78-0.73 (2H, m) 1-10
165-168 427 2.88 M2 (400 MHz, DMSO-d.sub.6) .delta.: 11.36 (1H, br
s), 8.46 (1H, d), 8.32 (1H, d), 7.76 (1H, dd), 7.61 (1H, s), 7.31
(1H, d), 6.75 (1H, s), 4.58 (2H, s), 3.35-3.33 (2H, m), 2.96-2.93
(2H, m), 2.32 (3H, s) 1-14 >280 408.2 0.97 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.9 (1H, s), 11.65 (1H, s), 8.7 (2H, s),
7.7 (1H, s), 3.4-3.45 (2H, m), 3.3-3.38 (4H, m), 2.95-3.05 (2H, m),
2.55-2.65 (3H, m) 1-52 229-232 300.2 0.62 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.34 (1H, s), 8.42 (1H, d), 7.54 (1H, s),
6.86 (1H, d), 3.27 (2H, d), 2.96 (2H, d), 2.41 (3H, s) 1-124
282-285 390.2 0.89 M1 (300 MHz, DMSO-d.sub.6) .delta.: 11.60 (1H,
s), 8.70 (2H, s), 7.72 (1H, s), 3.50-3.40 (4H, m), 3.20 (3H, s),
3.05-3.00 (2H, m), 1.10 (6H, s) 1-125 212-215 376.2 0.85 M1 (300
MHz, DMSO-d.sub.6) .delta.: 11.60 (1H, s), 8.70 (2H, s), 7.72 (1H,
s), 4.22-4.18 (2H, m), 3.60-3.50 (1H, m), 3.40-3.35 (2H, m), 3.22
(3H, s), 3.00-2.95 (2H, m), 1.15 (3H, d) 1-126 nd 388.2 0.84 M1
(300 MHz, DMSO-d.sub.6) .delta.: 11.60 (1H, s), 8.70 (2H, s), 7.72
(1H, s), 4.20-4.15 (1H, m), 3.80 (2H, q), 3.65 (1H, q), 3.55-3.40
(2H, m), 3.35 (1H, dd), 3.05-3.00 (2H, m), 1.90-1.75 (3H, m),
1.55-1.45 (1H, m) 1-127 229-231 383.2 0.77 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.20 (1H, s), 7.75 (1H, s), 7.60 (1H, dd),
6.85 (1H, d), 6.75 (1H, d), 4.20-4.15 (1H, m), 3.80 (1H, q), 3.65
(1H, q), 3.55-3.40 (3H, m), 3.35 (1H, dd), 3.05-3.00 (2H, m), 2.50
(3H, s), 1.90-1.75 (3H, m), 1.55-1.45 (1H, m) 1-128 234-237 394.2
0.79 M1 (300 MHz, DMSO-d.sub.6) .delta.: 11.95 (1H, s), 11.05 (1H,
s), 7.70 (1H, s), 7.55 (1H, dd), 6.82 (1H, d), 6.72 (1H, d), 6.12
(1H, s), 4.55 (2H, s), 3.30-3.25 (2H, m), 3.05-3.00 (2H, m), 2.40
(3H, s), 2.35 (3H, s) 1-129 261-263 376.4 0.85 M1 (300 MHz,
DMSO-d.sub.6) .delta.: d 11.82 (1H, s), 11.49 (1H, s), 8.52 (1H,
d), 7.67 (1H, s), 3.60-3.50 (4H, m), 3.43-3.35 (2H, m), 3.26 (3H,
s), 3.05-2.94 (2H, m), 2.44 (3H, d) 1-130 nd 375.0 0.61 M1 (300
MHz, DMSO-d.sub.6 + 0.1% TFA-d) .delta.: 8.84 (2H, s), 8.15 (1H,
s), 3.61-3.39 (4H, m), 3.22-3.07 (2H, m), 3.04-2.86 (2H, m), 2.62
(3H, s), 2.07-1.83 (2H, m) 1-131 249-251 376.2 0.85 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.80 (1H, s), 11.63 (1H, s), 8.69 (2H, s),
7.68 (1H, s), 4.24 (1H, s), 3.53 (1H, dd), 3.38 (1H, dd), 3.25 (5H,
m), 2.95 (2H, d), 1.15 (3H, d) 1-132 nd 362.2 0.70 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.64 (1H, brs), 8.69 (2H, s), 7.67 (1H, s),
3.47-3.30 (6H, m), 3.02-2.99 (2H, m), 1.77-1.72 (2H, m) 1-133
>220 406.3 0.77 M1 (300 MHz, DMSO-d.sub.6) .delta.: 11.83 (1H,
s), 11.63 (1H, s), 8.69 (2H, s), 7.67 (1H, s), 3.63 (2H, br t),
3.52 (4H, m), 3.47-3.36 (4H, m), 3.24 (3H, s), 3.00 (2H, br t)
1-134 246 376.2 1.70 M3 (300 MHz, DMSO-d.sub.6) .delta.: 11.83 (1H,
s), 11.64 (1H, s), 8.69 (2H, d), 7.67 (1H, s), 3.60 (2H, t), 3.53
(1H, d), 3.48-3.36 (4H, m), 3.00 (2H, dd), 1.11 (3H, t) 1-135 nd
480.2 0.66 M1 (300 MHz, DMSO-d.sub.6) .delta.: 11.86 (1H, bs), 8.69
(2H, s), 8.22 (1H, d), 7.70 (1H, s), 7.44- 7.08 (2H, m), 4.56 (2H,
s), 3.74 (4H, t), 3.13 (4H, t), 3.05-2.89 (2H, m), 2.62 (2H, d)
1-136 nd 417.3 0.57 M1 (300 MHz, DMSO-d.sub.6) .delta.: 11.82 (1H,
bs), 11.63 (1H, bs), 8.69 (2H, d,), 7.66 (1H, s), 3.60-3.53 (4H,
m), 3.50-3.42 (2H, m), 3.42- 3.35 (2H, m), 3.02-2.97 (2H, dd,),
2.60-2.53 (2H, m), 2.44-2.40 (4H, m) 1-137 283-286 350.2 0.81 M1
(300 MHz, DMSO-d.sub.6) .delta.: 11.90 (1H, s), 11.65 (1H, s), 8.70
(2H, s), 7.70 (1H, s), 4.74 (1H, m), 4.58 (1H, m), 3.77-3.58 (2H,
m), 3.43 (2H, m), 3.02 (2H, m) 1-138 245 400.2 0.80 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.60 (1H, s), 8.70 (2H, s), 7.70 (1H, s),
4.65 (2H, s), 3.55-3.45 (2H, m), 3.10-3.10 (2H, m), 2.55 (3H, s)
1-139 195-200 398.2 0.76 M1 (300 MHz, DMSO-d.sub.6) .delta.: 8.69
(2H, s), 7.73 (1H, s), 7.59 (1H, d), 6.13 (1H, d), 4.45 (2H, s),
3.79 (3H, s), 3.25-3.22 (2H, m), 2.95-2.92 (2H, m) 1-140 232 431.1
1.13 M3 (300 MHz, DMSO-d.sub.6) .delta.: 11.82 (1H, s), 11.64 (1H,
s), 8.69 (2H, d), 7.66 (1H, s), 3.58 (4H, s), 3.30 (2H, s), 3.01
(2H, t), 2.33 (6H, d), 1.79 (2H, d), 1.17 (1H, t) 1-141 nd 458.0
0.59 M1 (300 MHz, DMSO-d.sub.6 + 10% TFA-d) .delta.: 8.84 (2H, s),
8.07 (1H, s), 4.15-3.92 (2H, m), 3.87-3.33 (13H, m), 3.24-3.06 (2H,
m), 1.32 (6H, d) 1-142 266-267 376.2 0.82 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.82 (1H, brs), 11.64 (1H, brs), 8.69 (2H,
s), 7.67 (1H, s), 3.39-3.30 (6H, m), 3.23 (3H, s), 3.02-2.99 (2H,
m), 1.88-1.79 (2H, m) 1-143 198-202 439.3 0.70 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 8.70 (2H, s), 8.51 (1H, s), 7.84 (1H, d),
7.72 (1H, s), 7.51 (1H, d), 4.72 (2H, s), 4.46 (2H, s), 3.46-3.43
(2H, m), 3.31 (3H, s), 3.07- 3.04 (2H, m) 1-144 227 429.3 0.66 M1
(300 MHz, DMSO-d.sub.6) .delta.: 11.93-11.70 (1H, bs), 11.54 (1H,
s), 8.69 (2H, s), 7.65 (1H, s), 3.00 (2H, t), 2.28 (5H, dd), 1.75
(2H, t), 1.49 (4H, q), 1.45-1.27 (2H, m) + 5H under DMSO and water
peaks. 1-145 251 427.4 0.61 M1 (300 MHz, DMSO-d.sub.6) .delta.:
11.78 (1H, s), 11.57-10.91 (1H, m), 8.42 (1H, d), 7.65 (1H, s),
6.87 (1H, d), 3.57 (4H, t), 3.22- 3.08 (1H, m), 3.08-2.90 (2H, m),
2.42 (3H, s), 2.34 (4H, q), 1.78 (2H, q) + 5H under DMSO and water
peaks. 1-146 nd 396.2 0.77 M1 (300 MHz, DMSO-d.sub.6) .delta.:
11.85 (1H, s), 11.40 (1H, s), 8.40 (1H, d), 7.70 (1H, s), 6.90 (1H,
d), 4.65 (2H, s), 3.52-3.45 (2H, m), 3.10-3.0 (2H, m), 2.55 (3H,
s), 2.40 (3H, s). 1-147 >260 428.3 0.94 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.60 (1H, s), 8.70 (2H, s), 7.70 (1H, s),
4.70 (2H, s), 3.55-3.45 (2H, m), 3.25 (1H, q), 3.10- 3.00 (2H, m),
1.30 (6H, d). 1-148 238-240 465.3 0.67 M1 (300 MHz, DMSO-d.sub.6)
.delta.: 11.80 (1H, d), 11.64 (1H, s), 8.69 (2H, s), 7.65 (1H, s),
3.40-3.25 (4H, m), 3.14-2.87 (2H, m), 2.65-2.40 (2H, m) 2.39 (4H,
d), 1.94 (4H, dt), 1.77 (2H, t). 1-149 >290 364.2 0.84 M1 (300
MHz, DMSO-d.sub.6) .delta.: 11.84 (1H, s), 11.64 (1H, s), 8.70 (2H,
d), 7.68 (1H, s), 4.60 (1H, t), 4.43 (1H, d), 3.45 (2H, dd), 3.02
(2H, t), 2.01 (2H, dq). 1-150 nd 400.1 0.81 M1 (300 MHz,
DMSO-d.sub.6) .delta.: 11.91(1H, s), 11.67 (1H, s), 8.70 (2H, s),
7.69 (1H, s), 4.83 (2H, s), 3.65-3.45 (2H, m), 3.15- 3.00 (2H, m),
2.30 (3H, s). 1-151 272-273 479.2 0.63 M1 (300 MHz, DMSO-d.sub.6)
.delta.: 11.81 (1H, s), 11.62 (1H, s), 8.69 (2H, s), 7.87-7.44 (1H,
m), 3.46-3.33 (4H, m), 3.08 (4H, t), 3.01 (2H, t), 2.87 (4H, t),
1.77 (2H, dd) + 2H under water peak. 1-152 nd 392.2 0.70 M1 (300
MHz, DMSO-d.sub.6) .delta.: 11.38 (s, 1H), 8.72 (d, 2H), 8.43 (d,
1H), 7.66 (s, 1H), 7.33 (t, 1H), 6.88 (d, 1H), 4.79 (s, 2H), 3.65
(s, 2H), 3.07 (d, 2H), 2.43 (s, 3H). 1-153 223 459.3 0.63 M1 (300
MHz, DMSO-d.sub.6) .delta.: 11.78 (1H, s), 11.63 (1H, s), 8.69 (2H,
s), 7.66 (1H, s), 3.57 (2H, dd), 3.40-3.20 (4H, m), 3.07- 2.90 (4H,
m), 2.77-2.61 (2H, m), 1.68 (2H, t), 0.88 (6H, d).
Pharmacology
[0645] The compounds provided in the present invention are positive
allosteric modulators of mGluR.sub.4. As such, these compounds do
not appear to bind to the orthosteric glutamate recognition site,
and do not activate the mGluR.sub.4 by themselves. Instead, the
response of mGluR.sub.4 to a concentration of glutamate or
mGluR.sub.4 agonist is increased when compounds of Formula (I) to
(III) are present. Compounds of Formula (I) to (III) are expected
to have their effect at mGluR.sub.4 by virtue of their ability to
enhance the function of the receptor.
mGluR.sub.4 Assay on HEK-Expressing Human mGluR.sub.4
[0646] The compounds of the present invention are positive
allosteric modulators of mGluR.sub.4 receptor. Their activity was
examined on recombinant human mGluR.sub.4a receptors by detecting
changes in intracellular Ca.sup.2+ concentration, using the
fluorescent Ca.sup.2+-sensitive dye Fluo4-(AM) and a Fluorometric
Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale,
Calif.).
Transfection and Cell Culture
[0647] The cDNA encoding the human metabotropic glutamate receptor
(hmGluR.sub.4), (accession number NM 000841.1, NCBI Nucleotide
database browser), was subcloned into an expression vector
containing also the hygromycin resistance gene. In parallel, the
cDNA encoding a G protein allowing redirection of the activation
signal to intracellular calcium flux was subcloned into a different
expression vector containing also the puromycin resistance gene.
Transfection of both these vectors into HEK293 cells with PolyFect
reagent (Qiagen) according to supplier's protocol, and hygromycin
and puromycin treatment allowed selection of antibiotic resistant
cells which had integrated stably one or more copies of the
plasmids. Positive cellular clones expressing hmGluR.sub.4 were
identified in a functional assay measuring changes in calcium
fluxes in response to glutamate or selective known mGluR.sub.4
orthosteric agonists and antagonists.
[0648] HEK-293 cells expressing hmGluR.sub.4 were maintained in
media containing DMEM, dialyzed Fetal Calf Serum (10%),
Glutamax.TM. (2 mM), Penicillin (100 units/mL), Streptomycin (100
.mu.g/mL), Geneticin (100 .mu.g/mL) and Hygromycin-B (40 .mu.g/mL)
and puromycin (1 .mu.g/mL) at 37.degree. C.5% CO.sub.2.
Fluorescent Cell Based-Ca.sup.2+ Mobilization Assay
[0649] Human mGluR.sub.4 HEK-293 cells were plated out 24 hours
prior to FLIPR.sup.384 assay in black-walled, clear-bottomed,
poly-L-ornithine-coated 384-well plates at a density of 25,000
cells/well in a glutamine/glutamate free DMEM medium containing
foetal bovine serum (10%), penicillin (100 units/mL) and
streptomycin (100 .mu.g/mL) at 37.degree. C.5% CO.sub.2.
[0650] On the day of the assay, the medium was aspirated and the
cells were loaded with a 3 .mu.M solution of Fluo4-AM
(LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After
1 hour at 37.degree. C. 5% CO.sub.2, the non incorporated dye was
removed by washing cell plate with the assay buffer and the cells
were left in the dark at room temperature for six hours before
testing. All assays were performed in a pH 7.4 buffered-solution
containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mM MgSO.sub.4, 1
mM CaCl.sub.2, 0.125 mM sulfapyrazone and 0.1% glucose.
[0651] After 10 s of basal fluorescence recording, various
concentrations of the compounds of the invention were added to the
cells. Changes in fluorescence levels were first monitored for 180
s in order to detect any agonist activity of the compounds. Then
the cells were stimulated by an EC.sub.25 glutamate concentration
for an additional 110 s in order to measure enhancing activities of
the compounds of the invention. EC.sub.25 glutamate concentration
is the concentration giving 25% of the maximal glutamate
response.
[0652] The concentration-response curves of representative
compounds of the present invention were generated using the Prism
GraphPad software (Graph Pad Inc, San Diego, USA). The curves were
fitted to a four-parameter logistic equation:
(Y=Bottom+(Top-Bottom)(1+10 ((Log EC.sub.50-X)*Hill Slope)
allowing the determination of EC.sub.50 values.
[0653] The Table 3 below represents the mean EC.sub.50 obtained
from at least three independent experiments of selected molecules
performed in duplicate.
TABLE-US-00005 TABLE 3 Activity data for selected compounds
Compound Ca.sup.2+ no. Flux* 1-1 ++ 1-2 + 1-3 + 1-4 +++ 1-7 +++ 1-8
++ 1-10 +++ 1-14 ++ 1-52 +++ 1-124 ++ 1-125 +++ 1-126 +++ 1-127 ++
1-128 ++ 1-129 +++ 1-130 + 1-131 +++ 1-132 ++ 1-133 +++ 1-134 +++
1-135 +++ 1-136 ++ 1-137 +++ 1-138 +++ 1-139 ++ 1-140 +++ 1-141 +
1-142 +++ 1-143 +++ 1-144 ++ 1-145 +++ 1-146 +++ 1-147 +++ 1-148 ++
1-149 + 1-150 +++ 1-151 +++ 1-152 ++ 1-153 +++ *Table legend: +: 1
.mu.M < EC.sub.50 < 10 .mu.M ++: 100 nM < EC.sub.50 < 1
.mu.M +++: EC.sub.50 < 100 nM
[0654] The results shown in Table 3 demonstrate that the compounds
described in the present invention are positive allosteric
modulators of human mGluR.sub.4 receptors. These compounds do not
have activity by themselves but they rather increase the functional
activity and/or maximal efficacy of glutamate or mGluR.sub.4
agonist.
Haloperidol-Induced Catalepsy Model in the Rat
[0655] The haloperidol-induced catalepsy is a model of Parkinson's
disease. It is used to assess potential anti-parkinsonian action of
compound. In this model, haloperidol, a dopamine receptor
antagonist, is administered to induce catalepsy, characterized by
hypokinesia and rigidity. This state is described as an acute
parkinsonian state. Anti-parkinsonian drugs show efficacy in this
model by decreasing the catalepsy induced by haloperidol.
Experimental Design and Administration Procedure:
[0656] One day before the test, Male Sprague-Dawley rats (Charles
River, les Oncins, France) were placed in individual cages. The day
of the experiment, rats were injected with a dopamine D2 receptor
antagonist, haloperidol (1.5 mg/kg, i.p.) 30 minutes prior to oral
administration of test compound (1, 3, 10 and 30 mg/kg) or vehicle.
L-DOPA-benserazide (150 mg/kg) used as a positive control, was also
orally administered 30 min post-haloperidol injection.
Experimental Procedure-Catalepsy Test:
[0657] Catalepsy was assessed 60 minutes after test compound or
vehicle or MTEP treatments L-DOPA-benserazide using a grid test
(e.g. 90 min post-haloperidol administration). Briefly, the rats
were placed on a vertical wire grid with the head pointing toward
the ceiling and all paws gripping the grid. Latency to movement of
both forepaws to relocate the body was measured (in seconds) with a
maximum latency "cut-off" time of 120-seconds. Brain and plasma
were collected at the end of the experiment for compound exposure
assessment.
Unilateral 6-OHDA Lesion Treatments
[0658] The effect of test compounds were assessed alone or in
combination with L-DOPA in male Sprague-Dawley rats lesioned
through medial forebrain bundle (Taconic).
[0659] Animals were orally administered with test compounds and
then tested 55-65 min post dosing in the forelimb stepping test for
akinesia and 65-70 minutes post-dosing in the cylinder test. L-DOPA
(2, 6 or 20 mg/kg), used as positive control and in co-therapy were
ip injected. Then forelimb akinesia and cylinder tests were carried
out 30-45-minutes post-dosing. In co-therapy, rats received test
compound 30 minutes prior to L-DOPA and they were tested as
described above between 55 and 75 minutes post test compound
dosing.
Forelimb Stepping Test for Akinesia
[0660] Stepping movements made by the isolated ipsi- and
contra-lateral forelimbs are assessed. The rat's weight is centered
over the isolated limb with its head and forequarters oriented
forward by the experimenter. The number of rat-initiated steps that
shift weight to a new location are recorded for 30-s.
Cylinder Test
[0661] Measures spontaneous forelimb use while rats voluntarily
explore a cylinder (d: 20-25 cm; h: 30 cm) and scored for the
number of either ipsi-lateral, contra-lateral (affected limb), or
both paw contacts during exploratory movements
[0662] Preference scores are calculated for ipsi-, contra-, or both
forelimb contacts during a 10-minutes interval for a minimum of 20
events. For example, a zero score (lack of asymmetry) results from
equal number of events for independent ipsi-versus contra-contacts,
or simultaneous contacts of both paws.
[0663] Blood samples were taken immediately after testing.
Marble Burying Model of Anxiety
[0664] Anxiety models in rodents are used as standard tests to
demonstrate anxiolytic-like properties of novel compounds. Mice
exhibit a tendency to bury harmless novel objects when encountered
in a test cage. Marble burying behavior in mice is reduced by
compounds which are efficacious anxiolytics in humans. Thus, marble
burying in mice has been used as a model for the prediction of
anxiolytic-like effects of compounds (Millan, M. J. et al. (2002)
Neuropharmacology 42:677-684).
[0665] Male C57BL6j mice (20-30 g), 7 weeks of age at the time of
delivery were group housed in a temperature and humidity controlled
facility on a 12 hour light dark cycle for at least 5 days before
use. Mice had access to food and water ad libitum except during
marble burying experiments.
[0666] Assessment of marble burying: The effect of compounds on
marble burying in mice was tested. On the day of the test, animals
were marked on their tails and weighed in a separate preparation
room 1 hour before drug administration. Test compound or vehicle
was administered p.o. 60 minutes prior to the test session. Marble
burying was tested in a separate experimental room. For the test,
mice were placed individually into clear plastic cages
(16.times.22.times.14 cm) with 5 cm of sawdust and 10 marbles
evenly spaced against the walls of the cage. The mice were left
undisturbed in the cages for 30 minutes. After removal of the mice
from the test cages, the number of marbles buried was counted. A
marble was considered buried if it was 23 or more covered.
[0667] Compound administration: Test compounds were dissolved in a
solution of 100% PEG 400. Test compounds were administered by oral
gavage (p.o.) in a volume of 10 mL/kg. Compound and vehicle-treated
mice received the equivalent volume of vehicle solution p.o. in the
absence of added compound.
[0668] Statistical analyses: Statistical analyses were performed
using GraphPad PRISM version 4.01 statistical software (GraphPad,
San Diego, Calif., USA). Data were analyzed using one-way analysis
of variance (ANOVA) followed by Bonferroni-corrected multiple
comparisons, or t tests if only 2 groups were present. The
significance level was set at p<0.05.
[0669] Thus, the positive allosteric modulators provided in the
present invention are expected to increase the effectiveness of
glutamate or mGluR.sub.4 agonists at mGluR.sub.4 receptor.
Therefore, these positive allosteric modulators are expected to be
useful for treatment of various neurological and psychiatric
disorders associated with glutamate dysfunction described to be
treated herein and others that can be treated by such positive
allosteric modulators.
FORMULATION EXAMPLES
[0670] Typical examples of recipes for the formulation of the
invention are as follows:
1. Tablets
TABLE-US-00006 [0671] Active ingredient 5 to 50 mg Di-calcium
phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg
Potato starch ad 200 mg
[0672] In this Example, active ingredient can be replaced by the
same amount of any of the compounds according to the present
invention, in particular by the same amount of any of the
exemplified compounds.
2. Suspension
[0673] An aqueous suspension is prepared for oral administration so
that each 1 milliliter contains 1 to 5 mg of one of the active
compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium
benzoate, 500 mg of sorbitol and water ad 1 mL.
3. Injectable
[0674] A parenteral composition is prepared by stirring 1.5% by
weight of active ingredient of the invention in 10% by volume
propylene glycol and water.
4. Ointment
TABLE-US-00007 [0675] Active ingredient 5 to 1000 mg Stearyl
alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g
[0676] In this Example, active ingredient can be replaced with the
same amount of any of the compounds according to the present
invention, in particular by the same amount of any of the
exemplified compounds.
[0677] Reasonable variations are not to be regarded as a departure
from the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
* * * * *